Functional Significance of Cell Volume Regulatory Mechanisms

PHYSIOLOGICAL REVIEWS
Vol. 78, No. 1, January 1998
Printed in U.S.A.
Functional Significance of Cell Volume Regulatory Mechanisms
FLORIAN LANG, GILLIAN L. BUSCH, MARKUS RITTER, HARALD VÖLKL,
SIEGFRIED WALDEGGER, ERICH GULBINS,
AND DIETER HÄUSSINGER
Institute of Physiology, University of Tübingen, Tübingen; Department of Internal Medicine, University of
Düsseldorf, Düsseldorf, Germany; and Department of Internal Medicine and Institute of Physiology,
University of Innsbruck, Innsbruck, Austria
I. Introduction 248
II. Cell Volume Regulatory Mechanisms 248
A. Ions in steady-state maintenance of cell volume 249
B. Volume regulatory ion transport 249
C. Osmolytes 251
D. Further metabolic pathways contributing to cell volume regulation 252
III. Intracellular Signaling of Cell Volume Regulation 252
A. Macromolecular crowding 253
B. Cytoskeleton 253
C. Cell membrane stretch 254
D. Cell membrane potential 254
E. Cytosolic pH 255
F. Calcium 255
G. G proteins 255
H. Protein phosphorylation 256
I. Chloride 257
J. Magnesium 257
K. Eicosanoids 257
L. pH in acidic cellular compartments 258
M. Gene expression 259
IV. Challenges of Cell Volume Constancy 259
A. Alterations of extracellular osmolarity 259
B. Alterations of extracellular ion composition 260
C. Energy depletion 261
D. Ion transport altered by hormones and transmitters 261
E. Substrate transport 261
F. Metabolism 261
G. Others 264
V. Role of Cell Volume Regulatory Mechanisms in Cell Functions 264
A. Erythrocyte function 264
B. Epithelial transport 264
C. Regulation of metabolism 266
D. Receptor recycling 267
E. Hormone and transmitter release 267
F. Excitability and contraction 268
G. Migration 269
H. Pathogen host interactions 270
I. Cell proliferation 271
J. Cell death 272
K. Others 273
Lang, Florian, Gillian L. Busch, Markus Ritter, Harald Völkl, Siegfried Waldegger, Erich Gulbins, and
Dieter Häussinger. Functional Significance of Cell Volume Regulatory Mechanisms. Physiol. Rev. 78: 247–306,
1998.—To survive, cells have to avoid excessive alterations of cell volume that jeopardize structural integrity and
constancy of intracellular milieu. The function of cellular proteins seems specifically sensitive to dilution and
concentration, determining the extent of macromolecular crowding. Even at constant extracellular osmolarity,
volume constancy of any mammalian cell is permanently challenged by transport of osmotically active substances
0031-9333/98 $15.00 Copyright � 1998 the American Physiological Society
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LANG ET AL. Volume 78
across the cell membrane and formation or disappearance of cellular osmolarity by metabolism. Thus cell volume
constancy requires the continued operation of cell volume regulatory mechanisms, including ion transport across
the cell membrane as well as accumulation or disposal of organic osmolytes and metabolites. The various cell
volume regulatory mechanisms are triggered by a multitude of intracellular signaling events including alterations
of cell membrane potential and of intracellular ion composition, various second messenger cascades, phosphorylation
of diverse target proteins, and altered gene expression. Hormones and mediators have been shown to exploit
the volume regulatory machinery to exert their effects. Thus cell volume may be considered a second message in
the transmission of hormonal signals. Accordingly, alterations of cell volume and volume regulatory mechanisms
participate in a wide variety of cellular functions including epithelial transport, metabolism, excitation, hormone
release, migration, cell proliferation, and cell death.
I. INTRODUCTION 236, 309, 336, 387–391, 395, 400, 604, 698, 763, 792, 852,
970, 1121, 1138, 1168).
With only few exceptions (416), the membranes of Instead, the discussion focuses on the significance
animal cells are highly permeable to water (212, 776). of cell volume for the performance of mammalian cells.
Animal cell membranes cannot tolerate substantial hydro- Moreover, the paper stresses recent developments. For a
static pressure gradients, and water movement across more complete coverage of earlier literature, the reader
those membranes is in large part dictated by osmotic pres- may refer to previous reviews on cell volume regulation
sure gradients (406, 445, 608, 985, 1043). Thus any imbal- (114, 425, 539, 545, 682, 776, 778, 815, 817, 843, 911a, 971,
ance of intracellular and extracellular osmolarity is paral- 1061, 1168), osmolytes (63, 142, 144, 370), and the role of
leled by respective water movement across cell mem- cell volume in regulation of cell function (495, 693).
branes and subsequent alterations of cell volume. For various functions, experimental evidence point-
As outlined below, most mammalian cells are bathed ing to the involvement of cell volume and cell volume
in extracellular fluid with almost constant osmolarity. regulatory mechanisms is intriguing but far from conclu-
Nevertheless, considerable alterations of extracellular os- sive. It is hoped that this review stimulates further experimolarity
are encountered in a variety of diseases. Exces- mental effort in this exciting area of research to clarify
sive alterations of extracellular osmolarity occur in kidney
medulla during transition between antidiuresis and diuresis
(63).
the many remaining questions.
Even at constant extracellular osmolarity, cell volume
constancy is compromised by alterations of intracel-
II. CELL VOLUME REGULATORY MECHANISMS
lular osmolarity. A wide variety of metabolic pathways Rapid changes of cell volume are usually caused by
leads to cellular formation or dissipation of osmotically
active substances. Moreover, transport across the cell
movement of water across the cell membrane (Jv), which
is driven by a hydrostatic (Dp) and osmotic (Dp) pressure
membrane modifies cellular osmolarity and thus cell gradient and depends on the hydraulic conductivity of the
volume.
To avoid excessive alterations of cell volume, cells
cell membrane (Lp) have developed and utilize a multitude of volume regulatory
mechanisms including transport across the cell mem-
Jv Å Lp(Dp 0 Dp)
brane and metabolism. These mechanisms are triggered
by minute alterations of cell volume. They not only serve
to readjust cell volume but profoundly modify a wide vari-
ety of cellular functions. Thus cell volume is an integral
Dp depends on the effective concentration difference
across the cell membrane (Dc) and the reflection coefficient
(s) for each solute i
element within the cellular machinery regulating cellular
performance.
It is the aim of this review to illustrate the functional
Dp Å RTSsiDci significance of cell volume. To this end, a description of where R and T are the gas constant and the absolute
the volume regulatory mechanisms and the cellular func- temperature, respectively. Application of the equations
tions sensitive to cell volume is followed by a discussion would require that the cytosol behaves as a dilute solu-
of the role of cell volume in several integrated cell function. This is not entirely true, as discussed elsewhere in
tions. detail (194–196, 357, 722). The cell membrane does not
This review does not consider volume regulatory withstand hydrostatic pressure gradients exceeding 2 kPa
mechanisms in prokaryotic cells or comparative aspects (445), which is equivalent to 1 mmol/l Dc. Even though
of cell volume regulation, and the reader may refer to the interaction of the cell membrane with the cytoskeleton
respective pertinent literature (84, 96, 128, 175, 225, 232, may allow the hydrostatic gradient to become larger (382,
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January 1998 FUNCTIONAL SIGNIFICANCE OF CELL VOLUME 249
577, 828), the movement of water is mainly dictated by amino acids, or carbohydrate metabolites. The concentra-
osmotic gradients across the cell membrane.
tion of these substances is higher within the cells than in
The Lp depends on the presence of water channels extracellular fluid. The excess cellular concentrations of
(aquaporins) in the cell membrane, a family of molecules, these organic substances are counterbalanced by lower
which are inserted into the cell membrane and allow the intracellular ion concentration. Most cells extrude Na / in
exchange for K / by the Na / -K / passage of water (6, 214, 270, 300, 349, 356, 494, 536,
-ATPase. The cell mem-
565, 773, 980). The aquaporins are especially important brane is only poorly permeable to Na / , and the exclusion
of impermeable Na / in water transporting epithelia but may be expressed in
outweighs the cellular osmolarity
nonepithelial cells. Even though osmotically driven water created by impermeant organic solutes (double Donnan
transport is an obvious requirement for osmotic cell swell- hypothesis; Refs. 721, 776). On the other hand, the cell
ing and cell volume regulation, water movement across membrane is highly permeable to K / . The exit of K / cre-
the cell membrane is rarely a limiting factor in cell volume
ates an outside-positive cell membrane potential, which
changes. Thus alterations of intra- or extracellular osmo- drives Cl 0 out of the cell. The low intracellular Cl 0 concen-
larity are in general followed by the respective movements tration compensates for the excess intracellular concen-
of water and alterations of cell volume. tration of organic substances.
Inhibition of the Na / -K / Cell volume regulatory mechanisms are thus most
-ATPase with ouabain evenconveniently
disclosed by exposing cells to abrupt tually leads to cell swelling (see Table 2) because of dissipation
of the Na / and K / changes of extracellular osmolarity. If cells are exposed
gradients, depolarization of the
to hypotonic extracellular fluid, they initially swell as cell membrane, and subsequent entry of Cl 0 into the cells
(688, 779). However, inhibition of the Na / -K / more or less perfect osmometers but then approach the
-ATPase
original cell volume by so-called regulatory cell volume does not always lead to a rapid increase of cell volume,
decrease (RVD). If cells are exposed to hypertonic extra- which may remain constant (407, 779, 924, 1039) or even
cellular fluid, they initially shrink like almost perfect os- transiently decrease (16, 631, 919, 1131). A sequence of
events leading to cell shrinkage after inhibition of the Na / mometers but then may approach the original cell volume
-
by so-called regulatory cell volume increase (RVI). It K / -ATPase includes increase of intracellular Na / activity,
reversal of Na / /Ca 2/ should be kept in mind, however, that exposure of cells
exchange, increase of intracellular
to anisotonic extracellular fluid does not only modify cell Ca 2/ activity, subsequent activation of Ca 2/ -sensitive K /
volume but also the volume of intracellular organelles channels, hyperpolarization (despite decrease of intracel-
such as mitochondria (969). Furthermore, in parallel to lular K / activity), and cellular KCl loss. Obviously, the
cellular osmolarity, cellular ionic strength is altered even time required by ouabain to eventually cause cell swelling
if extracellular ionic strength is kept constant. Thus the depends on Na / entry. In thick ascending limb (519, 520,
sequelae of osmotic alterations of cell volume are not 1178) or diluting segment (444) of the nephron, for in-
necessarily identical to the consequences of isotonic alter- stance, swelling can be delayed by inhibition of Na / -K / -
2Cl 0 ations of cell volume.
cotransport.
Alterations of cell volume may be limited by con- Under the influence of ouabain, hepatocytes and re-
straints from extracellular tissue, as shown for the brain nal cortical cells are apparently able to maintain their
(1220), the heart (972), and renal proximal tubules (753, cell volume by electrolyte accumulation in intracellular
755). More important, however, is the ability of cells to vesicles, which are subsequently expelled by exocytosis
adjust intracellular osmolarity by ion movement across (1038, 1039, 1257–1260). The electrolyte accumulation is
accomplished by a H / -ATPase in parallel to Cl 0 the cell membrane and by generation, breakdown, uptake,
channels
or release of organic substances. (1039). At least theoretically, a H / -ATPase in the plasma
Ions contribute the bulk of intracellular (mainly K membrane could similarly maintain cell volume by creat-
/ )
and extracellular (mainly NaCl) osmolarity. Furthermore, ing a cell negative potential difference across the cell
membrane, thus driving Cl 0 ions contribute some two-thirds to cell volume regulation
after rapid alterations of extracellular osmolarity (331,
extrusion.
1266). Thus ion transport across the cell membrane is of
paramount importance for the regulation of cell volume.
Largely because of volume regulatory ion transport, RVD
B. Volume Regulatory Ion Transport
and RVI are accomplished within minutes after exposure As indicated above, ion transport across the cell
to anisotonic media.
membrane is the most efficient and rapid means of alter-
A. Ions in Steady-State Maintenance
of Cell Volume
ing cellular osmolarity. During cell swelling, cells extrude
ions, thus accomplishing RVD, whereas during cell
shrinkage, cells accumulate ions to achieve RVI. The acti-
To maintain their metabolic functions, cells have to vation of ion release during RVD is paralleled by inhibiaccumulate
a number of substances, such as proteins, tion of ion uptake mechanisms, and the ion uptake during
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LANG ET AL. Volume 78
RVI is paralleled by inhibition of ion release mechanisms. In many cells, swelling leads to the activation of non-
Thus the simultaneous stimulation of ionic mechanisms selective cation channels (for review, see Refs. 682, 1040,
for RVD and RVI is largely avoided (927, 938). A tremen- 1043). Because with the negative potential difference
dous amount of work has been dedicated to the elucida- across the cell membrane the net driving force for cation
tion of the ion transport systems in different tissues. A movement is directed into the cell, ion movement through
synopsis of tissue-specific transport systems is beyond these channels cannot be expected to directly serve cell
the scope of this review and has been reviewed in detail volume regulation. However, these channels allow the
passage of Ca 2/ elsewhere (682).
, which then enters the cells and activates
1. Regulatory cell volume decrease
Ca 2/ -sensitive K / channels (187, 1194, 1234).
Usually more cations (K / and Na / ) are lost from cells
than Cl 0 (436, 476, 998). The difference is partially due to
loss of HCO 0 3 . Most HCO 0 The transport systems most often activated by cell
3 lost is replaced by CO2, and
swelling are separate K / and anion channels. In several the H / thus generated is bound to intracellular buffers.
Thus the exit of HCO 0 studies, the anion channels activated by cell swelling have
3 is limited by the intracellular buffer
been found to be nonselective, allowing the passage not capacity (346, 738). The HCO 0 3 that is replaced by CO2
only of Cl does not directly contribute to cell volume regulation but
0 but also of HCO 0 3 (690, 1334) and even organic
anions and neutral organic osmolytes (176, 576, 632, 1034, allows the cellular loss of K / .
1169).
Osmotic cell swelling decreases the gap junctional
Obviously, different channel proteins from different conductance (890, 1002), an effect in part due to decrease
families are utilized for cell volume regulation. Among the of intracellular ion concentration.
cloned K / channels invoked to serve cell volume regula- Decreasing extracellular osmolarity activates Na /
tion are the Kv1.3 (N-type K channels in the frog skin (126, 226), urinary bladder (329,
/ channel) (273), the Kv1.5
channel (316), and the minK channel (150, 151). Cloned 740), and A6 cells (234), an effect, however, not related
Cl to cell volume regulation.
0 channels invoked in cell volume regulation include
the ClC-2 channel (435, 584, 585, 760, 1203), BRI-VDAC
(272), ICln (158, 439, 440, 910, 948, 949), and the P-glycoprotein
(or MDR protein) (362, 464, 1015, 1225, 1249, 1250).
2. Regulatory cell volume increase
Alternatively, P-glycoprotein (490, 532, 589, 590) and ICln The major ion transport systems accomplishing electrolyte
accumulation in shrunken cells are the Na / -K / (647) were suggested to regulate the volume regulatory
-
Cl 0 channel. However, the role of P-glycoprotein in cell 2Cl 0 cotransporter (294, 381) and the Na / /H / exchanger
volume regulation has been questioned (14, 15, 160, 256,
(420). The latter alkalinizes the cell leading to parallel
257, 663, 764, 988, 1217, 1269). Clearly, many of the proper- activation of the Cl 0 /HCO 0 3 exchanger. The H / and
HCO 0 3 exchanged for NaCl by the Na / /H / ties of cell volume regulatory anion channels are not ex-
exchanger and
plained by the known cloned channels (539), and addi- the Cl 0 /HCO 0 3 exchanger are replenished within the cell
tional anion channels must be operative. In addition,
from CO 2, which diffuses into the cell and is thus osmoti-
Na / (HCO 0 3 ) n cotransport may participate in RVD (1281). cally not relevant.
Among the cloned members of the Na / /H / Apart from ion channels, the most frequently utilized
exchanger
transport system for KCl exit is electroneutral KCl co- family (1294), NHE-1 (266), NHE-2 (266, 601), and NHEtransport
(708–710, 963, 1206; for review, see Ref. 682). 4 (107) are stimulated, whereas NHE-3 (86, 87, 266, 601)
This transporter appears to be activated preferably by is inhibited by cell shrinkage. The putative volume-sensi-
isotonic cell swelling (374). Some cells apparently release tive site at the NHE-1 molecule has been identified and is
KCl by parallel activation of K / /H / exchange and Cl 0 / distinct from the sites regulated by Ca 2/ and growth fac-
HCO tors (86). The cloned anion exchanger AE2 but not AE1
0 3 exchange (103, 161). The H / and HCO 0 3 exchanged
for KCl form CO2, which then diffuses out of the cell is postulated to participate in RVI (587).
Several members of the volume regulatory Na / -K / and is thus not osmotically active. Beyond that, the anion
-
exchanger (AE1) has been implicated in activation of vol- 2Cl 0 cotransporters have been cloned (265, 364, 951, 952,
1370). In muscle cells, NaCl cotransport rather than Na / ume regulatory ion channels (374, 861).
-
Swelling of Na / -rich erythrocytes is thought to stimu- K / -2Cl 0 cotransport is utilized for NaCl uptake (288).
late Na However, little is known about the volume regulatory role
/ extrusion through reversal of Na / /Ca 2/ exchange,
and parallel extrusion of Ca 2/ by the Ca 2/ -ATPase (932). of the cloned NaCl cotransporters (365).
Alternatively, evidence has been presented for the activa- In some cells, electrolyte accumulation during RVI is
tion of ouabain-insensitive Na / -ATPase or Na / -K / -ATPase accomplished by activation of Na / channels and/or nonse-
(850). Swelling has been shown to stimulate (1263) or
lective cation channels (159, 177, 1278, 1332). The depolar-
inhibit (1342) the Na / -K / -ATPase. The gastric K / -H / - ization induced by the Na / entry favors Cl 0 entry into the
ATPase is stimulated by cell swelling (1113).
cell.
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January 1998 FUNCTIONAL SIGNIFICANCE OF CELL VOLUME 251
On the other hand, cell shrinkage has been shown to acting the adverse effects of inorganic (such as K / ,Na / ,
and Cl 0 inhibit K ) and organic (such as spermine) ions (26, 138,
/ and Cl 0 channels, preventing cellular electro-
lyte loss through those channels (for review, see Ref. 682). 139, 213, 334, 662, 1271, 1351). Furthermore, betaine and
In several cell types, shrinkage has been observed to acti- glycerophosphorylcholine, and to a lesser extent inositol,
vate the Na / -K / -ATPase, which serves to replace accumu- counteract the destabilizing effect of urea on proteins
lated Na (145, 203, 384, 483, 750, 879, 966, 1119, 1380, 1382). For
/ with K / (for review, see Ref. 682).
Some cells do not undergo RVI during exposure to normal cell function, an appropriate balance must be
hypertonic extracellular fluid. The same cells, if exposed maintained between destabilizing (i.e., ions, urea) and sta-
to hypotonic extracellular fluid, show RVD, and if reex- bilizing (i.e., counteracting osmolytes) forces (19, 267,
posed to isotonic fluid, first shrink and then display RVI 807, 863, 1272, 1376, 1383). Accordingly, an increase of
(secondary RVI or RVI on RVD). In these cells, primary urea concentration specifically favors the parallel increase
RVI is presumably prevented by increased intracellular of glycerophosphorylcholine (723, 855, 966).
Cl 0 activity, as detailed in section IIII. Beyond their function in cell volume regulation, osmolytes
are protective against the destructive effects of
excessive temperatures (34, 292, 352, 383, 534, 579, 759,
C. Osmolytes 926, 989, 1058, 1160, 1193, 1200) and dessication (169,
The cellular accumulation of electrolytes after cell
232). Furthermore, they have been found to ease cell
membrane assembly (642).
shrinkage is limited because high ion concentrations inter- Cellular osmolyte accumulation can be achieved by
fere with structure and function of macromolecules, in- stimulated uptake, enhanced formation, or decreased degcluding
proteins (25, 139, 192, 193, 413, 491, 564, 573, 1376, radation. Decrease of intracellular osmolyte concentra-
1381). Furthermore, alterations of ion gradients across tion is accomplished by degradation or release. As comthe
cell membrane would affect the respective transport- pared with RVI accomplished by ions, accumulation of
osmolytes is a slow process taking hours to days.
ers. An increase of intracellular Na / activity, for instance,
would reverse Na / /Ca 2/ exchange and thus increase intracellular
Ca 2/ activity, which would in turn affect a multi- 1. Glycerophosphorylcholine
tude of cellular functions (1226).
To circumvent the untoward effects of disturbed ion
composition, cells produce so-called osmolytes, mole-
cules specifically designed to create osmolarity without
compromising other cell functions (37, 44, 141, 371, 384,
484, 629, 630, 714, 875, 1138, 1377, 1378). Unlike ions,
organic osmolytes even at high concentrations are com-
patible with normal macromolecular function. Thus the
term compatible osmolytes has been coined (129).
Three groups of osmolytes are used in mammalian
Glycerophosphorylcholine (GPC) is formed by deacylation
of phosphatidylcholine. The reaction is catalyzed
by a phospholipase A2, which is distinct from the
arachidonyl-selective enzyme (370, 371). Glycerophos-
phorylcholine is broken down by the GPC phosphodiesterase,
which degrades GPC to glycerol phosphate and
choline (370, 371). Increase of osmolarity by extracellular
addition of either NaCl or urea inhibits the phosphodies-
terase and thus leads to accumulation of GPC (1243).
cells: polyalcohols, such as sorbitol and inositol; methylamines,
such as glycerophosphorylcholine and betaine;
2. Sorbitol
and amino acids and amino acid derivatives, such as gly- Sorbitol is produced from glucose under the catalytic
cine, glutamine, glutamate, aspartate, and taurine (141, influence of aldose reductase (70, 321, 373), an enzyme
368, 370, 371, 629, 630, 714, 719, 724, 1077, 1381). Tissue- that is distributed in various tissues (104, 140, 217, 358,
specific utilization of the various osmolytes has been re- 614, 765, 856, 1053–1055, 1102, 1198). The enzyme is
viewed elsewhere in detail (682). upregulated by hypertonic extracellular addition of NaCl
Osmolytes are specifically important for cell volume or raffinose, but not of membrane-permeable solutes, such
regulation in renal medulla, where extracellular osmolar- as urea or glycerol. It is presumably an increase of cellular
ity may become more than fourfold that of isotonicity (62, ionic strength that stimulates the aldose reductase tran-
64–66, 99, 112, 141, 369, 399, 442, 452, 525, 666, 718, 724, scription rate (40, 230, 373, 599, 854, 1130, 1236). With
855, 1075, 1076, 1078, 1352, 1353, 1356, 1377, 1378), and continued hyperosmotic stress, the enzyme activity and
in the brain, where cell volume alterations cannot be toler- thus sorbitol concentration increases slowly, approaching
ated due to the rigid skull and where alterations of ion maximal values within 3 days (372). Osmolarity does not
composition would affect excitability (453, 524, 715–717, affect mRNA stability or enzyme degradation (39, 854).
745, 746, 915, 1155, 1166, 1167, 1170, 1220, 1221, 1266, The half-life of the enzyme is Ç6 days (372). Cell swelling
1270). stimulates the release of sorbitol (39, 377, 1345) through
Osmolytes not only replace ions as osmotically active putative channels, which are thought to be inserted into
species but also stabilize macromolecules, thus counter- the cell membrane by fusion of vesicles (629).
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LANG ET AL. Volume 78
3. Inositol of glutamine and glycine (496, 500) as well as cellular
Myo-inositol (inositol) is taken up into cells by a Na
release of several amino acids (540), at least partially
/ -
coupled transporter (81, 480, 666–668, 670, 1375). In-
creased cellular ionic strength (141) but not urea (878)
stimulates the transcription of the transporter and thus
cellular inositol accumulation (877, 1372). Similar to sorbitol,
inositol is rapidly released from swollen cells (354,
630).
through volume regulatory anion channels (176). Accordingly,
cellular amino acid concentration increases upon
cell shrinkage and decreases upon cell swelling (714). In
fibroblasts, the major amino acid accumulated is gluta-
mine (238, 239). Amino acids are probably important dur-
ing adaptation to minor changes of extracellular osmolarity.
Their contribution is, however, negligible for the adap-
4. Betaine
Betaine is accumulated in cells by a Na
tation to the excessive osmolarities in kidney medulla
(714).
/ -coupled
transporter (149, 1190, 1372, 1374). The carrier prefers g-
aminobutyric acid (GABA), which, however, is minimally
available in extracellular fluid (1374). Increased cellular
D. Further Metabolic Pathways Contributing to
Cell Volume Regulation
ionic strength (1242), but not urea (878), stimulates the
transcription rate of the transporter and thus betaine ac-
cumulation (876, 878, 1191, 1372). Betaine may further
be accumulated by choline oxidation, which is, however,
sensitive to cell shrinkage only in renal cortex (433, 758).
After cell swelling, betaine is rapidly released (354, 630).
In addition to amino acids, numerous organic metabolites
contribute to cellular osmolarity. Several metabolic
pathways known to be sensitive to cell volume may mod-
ify the concentrations of these metabolites and thus con-
tribute to cell volume regulation. Cell swelling increases
glycogen synthesis and inhibits glycolysis, thus decreasing
5. Taurine
the concentration of carbohydrate metabolites (12, 49, 50,
696, 819, 953). Furthermore, cell swelling has a relatively
Taurine is accumulated in cells by a Na weak stimulatory effect on lipogenesis (51). As detailed
/ -coupled
transporter (1239). The transcription of the transporter is in section VC, cell volume changes interfere with a great
stimulated by enhanced ionic strength, eventually leading number of other metabolic functions that to some extent
to cellular taurine accumulation (1238, 1240). After cell may modify cellular osmolarity. The overall impact of
swelling, taurine is rapidly released, presumably through these effects on cellular osmolarity is probably modest,
an anion channel (102, 540, 632, 671, 672, 678, 847, 1050, but the influence of cell volume on various metabolic path-
1087, 1238, 1240) which is, at least in Ehrlich ascites tumor ways is of paramount importance for regulation of metacells,
distinct from the volume regulatory Cl 0 channel bolic function (see sect. VC).
(677). In oocytes, expression of band 3-anion exchanger
tAE1 confers volume regulatory taurine transport (324,
374, 861), but in mammalian cells, taurine efflux is not
dependent on the presence of band 3 protein (1049). On
III. INTRACELLULAR SIGNALING OF CELL
VOLUME REGULATION
the other hand, taurine transport is induced by the insertion
of the peptide phospholemman (PLM) in lipid bilayers
(845).
Cell swelling and shrinkage exert profound effects
on intracellular signaling mechanisms, which in turn modify
a multitude of cellular functions including the volume
6. Amino acids
regulatory mechanisms. A great deal of experimental effort
has been spent in elucidating the intracellular machin-
In addition to taurine, the cellular concentration of ery underlying cell volume regulation. Frequently, the reseveral
other amino acids and amino acid metabolites is sult has been inconclusive for several reasons. 1) Not
modified by cell volume, including glutamine, glutamate, every effect of altered cell volume on intracellular signal-
glycine, proline, serine, threonine, b-alanine, (N-acetyl)- ing is related to regulation of cell volume. 2) Cells usually
aspartate, and GABA (for review, see Refs. 181, 682). Al- use several mechanisms in parallel, with different, parthough
the intracellular concentration of most individual tially overlapping cellular signaling mechanisms. 3) Differ-
amino acids is quite low, the sum of all amino acids sigent cells utilize distinct mechanisms, i.e., the information
nificantly contributes to cellular osmolarity in cells ex- gained in any given cell cannot necessarily be generalized
posed to isotonic extracellular fluid (714). Cell shrinkage to other cells. 4) Volume regulation requires mechanisms
stimulates Na / -coupled transport of neutral amino acids that are themselves not modified by cell volume changes
(182, 380, 1135, 1373) and proteolysis (498) and inhibits but rather permissive for activation of cell volume regulaprotein
synthesis (1159). Conversely, cell swelling inhibits tory mechanisms.
proteolysis and stimulates protein synthesis (498, 499, In the simplest case, an intracellular mechanism
1159). Furthermore, cell swelling stimulates breakdown serves cell volume regulation if it is modified by alter-
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January 1998 FUNCTIONAL SIGNIFICANCE OF CELL VOLUME 253
ations of cell volume, and a qualitatively and quantitatively erythrocyte Na / /Ca 2/ exchange (936), and hepatocyte K /
channels (474) and to inhibit Na / /H / identical modification of this intracellular mechanism trig-
exchanger in erythgers
the appropriate alterations of cell volume. This re- rocytes (936) and adenosine 3�,5�-cyclic monophosphate
(cAMP) production (58), Na / /H / quirement frequently is not met. If the identical modifica-
exchanger (732), and
tion does not trigger respective alterations of cell volume, Na / -K / -2Cl 0 cotransport (595) in thick ascending limb
the participation of a mechanism in cell volume regulation cells, thus leading to cell shrinkage. In erythrocytes, the
still cannot be ruled out, since the mechanism may require effect of urea was reversed by okadaic acid, pointing to
the collaboration of other mechanisms to be effective.
Similarly, the use of inhibitors, even if they are specific,
the involvement of phosphorylation (936).
does not lead to conclusive results. On the one hand,
inhibition of cell volume regulation by elimination of a
B. Cytoskeleton
given element of intracellular signaling (e.g., inhibition of
protein kinases or removal of Ca
1. Actin filaments
2/ ) does not discriminate
between volume regulatory and permissive mechanisms. Obviously, cell swelling or shrinkage will affect the
On the other hand, cell volume regulation may prove in- cytoskeletal architecture. In fact, actin filaments have
sensitive to elimination of a volume regulatory mechanism been found to be depolymerized during swelling of a vari-
if other mechanisms operating in parallel are strong ety of cells (89, 220–223, 241, 477, 478, 527, 736, 830, 831,
enough to replace the defect. Further examples could be 848, 1209, 1398), an effect which is at least partially due
to Ca 2/ given, each of which illustrates that the experimental elu- (223). Calcium concentration increases in most
cidation of the complex machinery serving cell volume cells after osmotic swelling (see sect. IIIF). As a result,
Ca 2/ regulation is extremely difficult.
depolymerizes actin filaments by binding to gelsolin
Even though our understanding of the intracellular (1161, 1327). Depolymerization could further result from
machinery mediating cell volume regulation is still incom- degradation of phosphatidylinositol 4,5-bisphosphate,
plete, knowledge of the interaction between cell volume, which inhibits depolymerization by interaction with pro-
elements of cellular signaling, and cell volume regulatory filin (703, 704). A transient depolymerization of the actin
mechanisms is mandatory for understanding the role of filaments may be followed by a polymerization of actin
cell volume for cell function.
filaments (1398). In hepatocytes, polymerization of actin
filaments prevails (1202) and is paralleled by expression
of b-actin (1097, 1202). The de novo actin biosynthesis is
A. Macromolecular Crowding probably the result of actin polymerization, since it is
inhibited by depolymerized actin (993).
Cell swelling leads to dilution and cell shrinkage to Cytoskeletal elements may interfere in several ways
concentration of cellular constituents including proteins. with volume regulatory mechanisms. Actin filaments may
The concentration of intracellular proteins markedly in- inhibit osmotically driven water fluxes (566, 567) and thus
fluences their function (131, 353, 376, 834, 836, 937, 1011). retard osmotically induced cell volume changes. Beyond
In erythrocytes, the volume regulatory set point can in- that, RVD is inhibited in several tissues by cytochalasin
deed be varied by manipulation of intracellular protein D (89, 221, 222, 224, 289, 340, 363, 619, 754, 1258), which
concentration (835, 837, 1397). The set points of both the interferes with actin assembly (781, 1161). Moreover, ex-
KCl symport (835, 838) and the Na / /H / exchanger (209, pression of actin binding protein was required for RVD in
210, 940) appear to be determined by macromolecular melanoma cells (166). Thus an intact actin filament netcrowding.
It has been suggested that among the enzymes work is required for activation of at least some of the
sensitive to ambient protein concentration is a kinase that volume regulatory mechanisms. In fibroblasts, actin depo-
is inactivated by protein dilution during cell swelling and lymerization reverses the shrinking effect of bradykinin
activated by protein crowding during cell shrinkage (835, into a swelling effect, again pointing to a role of actin
838). This kinase may inhibit the volume regulatory KCl filaments in cell volume control (1001, 1004). Via other
cotransport. Its inactivation during cell swelling would cytoskeletal elements, such as spectrin and ankyrin, actin
then disinhibit volume regulatory KCl efflux. filaments couple to membrane proteins, an interaction
Because of interaction of proteins with ambient elec- modified by cell volume changes. For instance, cell swelltrolytes,
macromolecular crowding is reduced by increas- ing stimulates binding of ankyrin to the anion exchanger
ing ionic strength, which indeed shifts the volume regula- band 3 protein (868). Another putative target of the actin
tory set point to smaller volumes (942). filament network is a K / channel that cannot be activated
Similarly, urea decreases the thermodynamic activity in isolated membrane vesicles devoid of cytoskeleton
of proteins and thus reduces macromolecular crowding (423). Furthermore, it has been shown that actin filament
fragments regulate Na / (211, 574, 723, 837, 978, 984, 1376). Urea has been shown
channels (77), and it has been
to activate erythrocyte KCl transport (293, 596, 936), speculated that the cytoskeleton may participate in the
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LANG ET AL. Volume 78
insertion of cell volume regulatory channels into the tion (857, 1043). Most of these channels, however, are
nonselective cation channels, allowing the passage of K / plasma membrane (340, 741), in the regulation of channels
,
by kinases (see sect. IIIH) and phospholipids (see sect. Na / , and Ca 2/ (for review, see Refs. 682, 1043). Because of
IIIK), and in the activation of channels by membrane the cell-negative cell membrane potential, the respective
stretch (1040). However, disruption of the actin network electrochemical gradients favor the cellular accumulation
of Na / and Ca 2/ rather than cellular loss of K / did not prevent activation of channels by cell membrane
. Thus
stretch (1133). Furthermore, the stimulation of taurine or these channels are not likely to directly serve cell volume
inositol release during cell swelling was not affected by regulation, and inhibition of these channels by gadolinium
cytochalasin B (626, 848). has been shown to decrease osmotic swelling and favor
The depolymerization of the actin filament network regulatory decrease of cell volume (1173). On the other
may participate in the activation of a mechanosensitive hand, Ca 2/ entering the cells through these channels is
thought to activate Ca 2/ -sensitive K / anion channel (832, 1108, 1227). Furthermore, depolymer-
channels (187, 1194,
ization of submembranous actin filaments may facilitate 1234).
the fusion of channel-containing vesicle membranes with The mechanism linking membrane stretch to activa-
the plasma membrane. Agonist-induced exocytosis has tion of the channels has not been clearly defined (1043).
indeed been shown to be favored by actin depolymeriza- Under discussion are 1) release of fatty acids from the
tion (32, 130, 147, 283, 954). stretched membrane and subsequent activation of stretch-
The cytoskeleton is further thought to be involved in sensitive channels by these fatty acids (917) and 2)
the volume regulatory activation of the Na / /H / exchanger stretch-induced activation of some element of the cy-
(106, 404, 431, 1292), which does contain putative cytoskeleton, such as spectrin (1133). Because stretch entoskeletal
binding sites (333). Actin depolymerization by hances channel open probability in the cell-free excised
either cell swelling or by addition of cytochalasin B, how- patch configuration (1043), cytosolic components are ap-
ever, activates the Na / -K / -2Cl 0 cotransporter (541, 586, parently not required for channel activation.
813), and in vesicles devoid of cytoskeleton, the Na / -K / -
2Cl
It is debatable whether stretch-activated channels par-
0 cotransporter is permanently active (541). This acti- ticipate in the fine-tuning of cell volume, since considerable
vation is counterproductive during the initial phase of cell stretch is required to activate these channels (1043). Possi-
swelling. bly, these channels may represent a last line of defense
In addition to its role in regulation of ion transport, against excessive cell swelling but are not involved in the
the cytoskeleton may mediate some effects of cell volume
on gene expression (76, 529).
response to moderate changes of cell volume.
2. Microtubules
D. Cell Membrane Potential
Cell swelling increases microtubule stability and
stimulates the expression of tubulin (511).
Colchicine, which disrupts the microtubule network,
inhibits RVD in Jurkat cells, HL-60 cells, and peripheral
The influence of cell swelling on cell membrane po-
tential depends on the ion channels preferentially activated
or inactivated and on the potential difference before
cell swelling. Activation of K / neutrophils (289), but not in Ehrlich ascites tumor cells
(223), kidney cells (924), and gallbladder (340). In macro-
phages, disruption of microtubules was found to activate
anion channels (821).
An intact microtubule network was found to be crucial
for the influence of cell volume on alkalinization of
intracellular vesicles (156, 1089), proteolysis (156, 1284),
and taurocholate exit from liver cells (508).
channels and a low initial
cell membrane potential favor hyperpolarization, whereas
activation of anion or nonselective cation channels and a
high initial cell membrane potential would favor depolar-
ization. After cell swelling, hyperpolarization of the cell
membrane is seen in hepatocytes (406), depolarization of
the cell membrane in Ehrlich ascites tumor cells (680,
691), Madin-Darby canine kidney (MDCK) cells (947),
opossum kidney cells (1235), lymphocytes (418, 419,
1060), pancreatic b-cells (124), astrocytes (627), neuro-
C. Cell Membrane Stretch
blastoma cells (313), and vascular smooth muscle cells
(685). In some cells, a transient hyperpolarization due to
activation of K / A variety of ion channels are activated by cell mem-
channels is followed by a more sustained
brane stretch, i.e., increased tension of the cell membrane depolarization due to activation of anion channels (516–
(1040, 1043). Stretch increases the open probability of the 518, 1002).
channels without affecting single-channel conductance or The alteration of cell membrane potential may influselectivity
of the channels (1043).
ence the activity of additional ion channels. A depolariza-
The stretch-activated channels may be selective for tion of the cell membrane may open voltage-sensitive ion
channels. In lymphocytes, RVD involves n-type K / K chan-
/ or for anions, thus directly serving cell volume regula-
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January 1998 FUNCTIONAL SIGNIFICANCE OF CELL VOLUME 255
nels (273, 429), which are activated by cell membrane
depolarization. Depolarization of the cell membrane may
further activate voltage-sensitive Ca 2/ channels, as ob-
served in pancreatic b-cells (124) and vascular smooth
muscle cells (685). The increase of intracellular Ca 2/
could trigger a variety of further mechanisms, as illus-
trated in section V, E and F.
As discussed in section IIB, increase of extracellular
osmolarity may either depolarize or hyperpolarize cells
due to activation of unspecific cation channels or inhibi-
The increase of [Ca 2/ ] i accounts for the activation of
Ca 2/ -sensitive K / channels, as shown in Ehrlich ascites
tumor cells (188), MDCK cells (1334), proximal tubule
cells (290, 605), thick ascending limb cells (1194), choroid
plexus epithelial cells (187), and neuroblastoma cells
(313). In MDCK cells, [Ca 2/ ]i did not appreciably increase
upon moderate osmotic cell swelling, even though the
Ca 2/ -sensitive K / channels were already activated by this
treatment (1002). Possibly small, localized increases of
[Ca 2/ ] i are sufficient to activate the K / tion of K
channels but are
not detected by fluorescence measurements (1357).
/ and/or Cl 0 channels.
Despite the activation of Ca 2/ -sensitive K / channels,
RVD is apparently not mediated by a rise of [Ca 2/ E. Cytosolic pH
]i in
Ehrlich ascites tumor cells (1204), and swelling-induced
K / efflux was virtually unaffected by the inhibitors of the
Cell swelling leads to cytosolic acidification (216, 397, Ca 2/ -sensitive K / channels, clotrimazole and charybdo-
479, 610, 616, 685, 757, 864, 1002, 1089, 1143, 1279), which toxin (489). Because these K / channels are inwardly rectihas
been explained by the exit of HCO 0 3 through anion fying (1334), K / exit through these channels during cell
channels (1334), by release of H / from acidic intracellular swelling may be limited by the depolarization of the cell
compartments (see sect. IIIL), and by enhancement of Cl 0 / membrane. Other less inwardly rectifying K / channels
HCO 0 3 exchange due to decreasing cellular Cl 0 activity may thus be more important for cell volume regulation in
those cells (539). In a variety of tissues, increase of [Ca 2/ (757). This latter mechanism, however, should be im-
] i
peded by inhibition of the exchanger at acidic cytosolic was not required for RVD (for review, see Ref. 682).
Clearly, activation of K / channels by Ca 2/ pH (645), and cellular acidosis is not inhibited by removal
may contribute
of extracellular Cl to, but is frequently not crucial for, RVD (539).
0 , at least in osteosarcoma cells (864).
In contrast to volume regulatory K / Cell shrinkage is frequently observed to alkalinize
channels in many
tissues, volume regulatory Cl 0 cells, at least partially due to activation of volume regula-
channels have been found
to be insensitive to Ca 2/ tory Na in intestinal cells (517, 657), cili-
/ /H / exchange (see sect. IIB).
The impact of intracellular pH on volume regulatory ary epithelial cells (1385), cardiac myocytes (1227), T84
mechanisms has not been explored. After cell swelling, colon carcinoma cells (1134, 1364), airway epithelial cells
the cytosolic acidification may impede activation of vol- (361, 1134), MDCK cells (48, 1029, 1334), lymphocytes
ume regulatory K (421), Ehrlich cells (188), and chromaffin cells (287). Yet,
/ channels (783) and may contribute to
as shown in Ehrlich ascites tumor cells, Ca 2/ inhibition of glycolysis and thus to the decreased release
triggers the
of lactic acid (696). The alkalinization after cell shrinkage formation of leukotrienes, which do activate the channels
(539). In kidney cortex, Ca 2/ -sensitive Cl 0 should stimulate glycolysis (696).
channels have
been found in endosomes and proposed to serve cell volume
regulation (991). Calcium is also thought to trigger
F. Calcium the fusion of vesicles, allowing the release of sorbitol
(629), whereas it is apparently not required for release of
After cell swelling, intracellular Ca 2/ concentration GPC (629) or taurine (1051).
([Ca 2/ ] i) increases in a variety of cells, whereas it remains Calmodulin antagonists and inhibitory peptides
apparently constant in others (for review, see Refs. 682, against Ca 2/ /calmodulin-dependent kinase (116) have
815). Swelling may increase [Ca 2/ ] i by both activation of been shown to inhibit RVD or activation of cell volume
Ca 2/ -permeable channels in the cell membrane and Ca 2/
regulatory ion channels (71, 263, 421, 424, 543, 546, 815),
release from intracellular stores. Calcium-permeable and it has been concluded that calmodulin/Ca 2/ comchannels
may be activated by cell membrane stretch (see plexes are important for activation of RVD. In other cells,
however, Ca 2/ -sensitive K / sect. IIIC), cell membrane depolarization (see sect. IIID),
channels involved in cell voland/or
protein kinase C (1066). Calcium release from in- ume regulation did not require calmodulin and were actu-
tracellular stores is presumably triggered by inositol phos- ally activated by calmodulin antagonists (950).
phates (52, 72, 1180, 1288, 1289) or Ca Beyond its putative role during RVD, calmodulin has
2/ -induced Ca 2/
been implicated in activation of the Na / -K / -2Cl 0 release (516, 518). The regulation of [Ca cotrans-
2/ ] i by cell volume
may interfere with signaling of Ca port in RVI (583).
2/ -recruiting hormones,
as shown for gastric parietal cells (885) and HT-29 cells
(330). In those cells, agonist-induced entry of Ca
G. G Proteins
2/ was
further stimulated by cell swelling (330, 885) and inhibited Inhibitors of G proteins such as pertussis toxin or
by cell shrinkage (885). cholera toxin have been shown to blunt the RVD (539) as
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LANG ET AL. Volume 78
well as swelling-induced osmolyte efflux (1037), increases Cl 0 channels and K / channels. To the extent that in those
of intracellular Ca cells cAMP is increased after cell swelling, cAMP partici-
2/ concentration (30), mitogen-activated
protein kinase (MAPK) activity (895, 1072), vesicu- pates in cell volume regulation. Beyond that, cAMP has
lar acidification (1088), and swelling-induced stimulation been postulated to shift the volume regulatory set point
of taurocholate excretion (895), suggesting that G proteins of the channel toward smaller volumes (823).
do mediate some effects of cell swelling. Activation of Additional experimental evidence points to the
the Na / /H / exchanger during cell shrinkage has similarly involvement of various kinases in volume regulation of
been claimed to involve G proteins (108, 249).
different cell types. In intestinal cells, volume regulatory
In addition to heterotrimeric G proteins, small G pro- rubidium efflux was inhibited by herbimycin A and gen-
teins have been implicated in cell volume regulation. Closistein, pointing to involvement of tyrosine kinase (1211).
tridium botulinus C3 exoenzyme, which depolymerizes Swelling of Jurkat cells activates the src-like tyrosine kinase
p56 lck the actin filament network by ADP-ribosylation of rho
, which in turn accounts for the activation of
(8), blunts the volume regulatory anion efflux (1209). In the volume regulatory Cl 0 channels (727a). Wortmannin,
neurons, osmotic cell shrinkage stimulates the expression an inhibitor of PI 3-kinase, similarly interferes with cell
of a1-chimerin (286), a GTPase-activating protein that in- volume regulation in those cells (1209). In proximal tubules
activates the small G protein Rac. The impact of this effect (1012–1014) and in HeLa cells (490), protein kinase C has
on cell volume regulation is not explored. been invoked to link cell swelling to activation of Cl 0 channels.
Cell swelling leads to phosphorylation of the anion
H. Protein Phosphorylation
exchanger, which was postulated to release taurine (869).
In addition to its role in the phosphorylation of pro-
1. Cell swelling
teins, ATP may serve as a signaling molecule itself. The
volume regulatory Cl 0 channel in collecting duct, glioma,
Mechanical stress or cell swelling has been found to and intestine 470 cells (908, 1277) as well as taurine efflux
stimulate protein kinase C (997, 1017) to foster tyrosine in skate hepatocytes and glioma cells (47, 575, 1277) are
phosphorylation of several proteins including focal adhe- apparently regulated by intracellular ATP concentration.
sion kinase p125 FAK (1209, 1211), to stimulate phosphati- Decreased ATP concentration, as it occurs during energy
dylinositol 3-kinase (PI 3-kinase) (1209), and to trigger depletion, inhibited the channel. In pancreatic b-cells, cell
MAPK cascades leading to the activation of Jun-NH2-ter- swelling leads to activation of ATP-sensitive K / channels
minal kinase (JNK) or extracellular signal-regulated ki- (289a). Extracellular ATP has been shown to stimulate
nases ERK-1 and ERK-2 (4, 360, 482, 568, 569, 895, 1044, taurine release from tracheal cells (362). It has been spec-
1072, 1073, 1127, 1211). Adenylate cyclase has been reulated that after cell swelling ATP is extruded via the
ported to be stimulated (851, 1324–1326) and inhibited cystic fibrosis transmembrane conductance regulator and
activates K / channels and Cl 0 (535) by cell swelling, and cAMP has been shown to inhibit
channels from the extracelvolume
regulatory Cl 0 channels in chicken hearts (468). lular side (1030, 1310). On the other hand, extracellular
ATP has been shown to inhibit volume regulatory Cl 0
Most recently, we have successfully cloned a cell volumeregulated
serine/threonine kinase, the human serum glucocorticoid-dependent
kinase h-sgk (1295). Expression of
channels in intestinal cells (1228).
this kinase is rapidly upregulated by moderate cell shrinkage
and markedly depressed by moderate cell swelling.
2. Cell shrinkage
How these events link to activation of the various Similar to cell swelling, osmotic cell shrinkage has
volume regulatory mechanisms is poorly understood. The been shown to activate protein kinase C (702), whereas
volume regulatory KCl cotransport is activated by dephos- cAMP formation (648) and cAMP-dependent phosphoryla-
phorylation and inactivated by phosphorylation (94, 295, tion have been shown to remain unaffected (13, 648). In
580, 581, 597, 920, 1144). Swelling or increased hydrostatic several cell types, osmotic shrinkage stimulates the phos-
pressure was suggested to inhibit a kinase, favoring dephorylation of myosin light chains, an effect presumably
phosphorylation (94, 295, 386, 580), but nothing is known related to activation of Na / -K / -2Cl 0 cotransport (635, 903,
about the properties of this kinase, which appears to be 1188).
distinct from protein kinases A and C (581). Some evi- Excessive osmotic cell shrinkage, such as doubling
dence indicates the involvement of the cytoskeleton in of extracellular osmolarity, triggers several proteins in-
the swelling-induced inhibition of the kinase (539). On the volved in the MAPK pathways, such as Raf-1, MAPK ki-
other hand, the view that phosphorylation or dephosphornase, MAPK, and ribosomal protein S6 kinase (809, 1197)
ylation links cell swelling to activation of KCl cotransport or activation of JNK by the MAPK kinase MKK4 (853),
has been challenged (1041).
which may be triggered by the tyrosine kinase Pyk2
The volume of a wide variety of cells is decreased by through a pathway requiring activation of PI 3-kinase and
cAMP (see Table 2), an effect mainly due to activation of the small G proteins Ras and Rac (1216). The activation
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January 1998 FUNCTIONAL SIGNIFICANCE OF CELL VOLUME 257
of MAPK pathways may be secondary to clustering and Decreased intracellular Cl 0 activity is apparently required
for full activation of Na / -K / -2Cl 0 internalization of cytokine receptors with subsequent acti-
cotransport durvation
of downstream targets (1020). On the other hand, ing cell shrinkage (539, 548, 1245, 1370). Beyond its influence
on one of the driving forces of Na / -K / -2Cl 0 the ribosomal protein S6 has been reported to be dephoscotransphorylated
upon osmotic cell shrinkage (656). port, a decreased intracellular Cl 0 concentration is
As shown in several tissues, cell shrinkage stimulates thought to play a permissive role for the activation of both
serine and threonine phosphorylation of the Na / -K / -2Cl 0 Na / -K / -2Cl 0 cotransport (119, 734, 735, 1009) and Na / /
cotransporter (636, 772, 927, 968, 1219). Volume-regulated
H / exchange (108, 250, 933, 934, 1009). If extracellular
Na / -K / -2Cl 0 cotransport may be activated (812, 814, 968) osmolarity is made hypertonic by increased extracellular
NaCl concentration, the increase of intracellular Cl 0 or inhibited (728) by cAMP, and cAMP does not particiactivpate
in activation of this carrier during cell shrinkage ity could thus impede RVI (539). Accordingly, some cells
(381). The protein kinase C inhibitor chelerythrine (702), are unable to regulate their volume during exposure to
but not staurosporine (583, 919), inhibits volume regula- hypertonic extracellular fluid (308, 437, 522, 539, 544, 545,
634). If intracellular Cl 0 tory Na is lowered by prior RVD (308,
/ -K / -2Cl 0 cotransport, which may be activated
(583) or inhibited (728) by phorbol esters. The involve- 420, 522, 634) or by activation of Cl 0 channels with cAMP
ment of protein kinase C in the activation of this carrier (437, 1177) or vasopressin (351, 519, 1177), the same cells
is thus a matter of debate. do accomplish RVI. Moreover, if cells are exposed to
Even though the Na short-chain fatty acids, they swell by accumulation of the
/ /H / exchanger is activated by
phosphorylation (88), phosphorylation of the carrier is acids along with Na / and are forced to release Cl 0 for
not affected by cell shrinkage (430) and not required for RVD (see Table 2). In the presence of these acids, they
activation (430). In Ehrlich ascites tumor cells, shrinkage- display RVI after exposure to hypertonic extracellular
induced activation of the transporter has been reported fluid (1016).
to be blunted by inhibition of protein kinase C and stimu- Intracellular Cl 0 inhibits the glycogen synthase phosphatase
(408), and the decrease of intracellular Cl 0 lated by inhibition of phosphatases (956). In dog erythroactivcytes,
inhibition of phosphatases shifted the set point of ity participates in the stimulation of glycogen synthesis
the Na during osmotic or glutamine-induced cell swelling (555,
/ /H / exchanger to higher volumes (941). However,
protein kinase C appeared not to be involved in activation
of the carrier in other tissues (108, 244, 422, 426, 427).
819).
The role of MAPKs in triggering of cell volume regulatory
mechanisms remains elusive, whereas their involve-
J. Magnesium
ment in regulation of betaine transporter expression has
been ruled out (669).
In yeast, histidine kinases are activated by enhanced
The dilution and concentration of intracellular sol-
utes during cell swelling or shrinkage lead to the respective
alterations of Mg 2/ osmolarity and trigger a cascade involving a MAPK-like
protein (791). Up to now, attempts to identify a volumeregulated
histidine kinase in mammalian cells have failed.
concentration. Magnesium has
been described to inhibit volume regulatory KCl cotransport
(78, 295). During cell swelling, the decrease of intra-
cellular Mg 2/ concentration may partially account for the
activation of KCl cotransport (78, 295). Conversely, an
increase of intracellular Mg 2/ activity stimulates Na / /H /
I. Chloride
exchange (944) and Na / -K / -2Cl 0 cotransport (794) and
may thus participate in regulatory cell volume increase.
As pointed out in section IIA, intracellular Cl 0 activity
is kept low, and this counterbalances the high intracellular
osmolarity created by organic substances. During osmotic K. Eicosanoids
cell swelling, intracellular Cl 0 activity is expected to de-
crease further due to H2O entry during the swelling phase Cell swelling has been shown to activate phospholi-
and Cl pase A2 (542, 800), possibly in part through decrease of
0 release during RVD. Intracellular Cl 0 activity is
similarly expected to decrease during swelling by cumula- macromolecular crowding (539). Metabolites of arachi-
tive substrate uptake, but it should increase during swelldonic acid include the products of cyclooxygenase (e.g.,
ing by depolarization of the cell membrane or after stimu- prostaglandins), 15-lipoxygenase (such as hepoxilin A3), lation of Na 5-lipoxygenase [e.g., leukotriene (LT) D4], and epoxygen-
/ -K / -2Cl 0 cotransport.
Osmotic cell shrinkage is expected to increase intra- ase (epoxyeicosatrienoic acids) (675). On the other hand,
cellular Cl as shown in Ehrlich ascites tumor cells, swelling stimu-
0 activity due to cellular H2O loss during the
shrinking phase and Cl 0 accumulation during RVI. On the lates the formation of the leukotrienes, namely, LTD4, at
other hand, intracellular Cl the expense of prostaglandins such as prostaglandin (PG)
0 activity should decrease during
shrinkage caused by activation of ion channels. E2 (675). Both phospholipase A2 and 5-lipoxygenase are
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LANG ET AL. Volume 78
activated by Ca 2/ (542, 675). Thus an increase of intracel- noic acids (818), indicating that the inhibitory effect on
lular Ca osmolyte flux is not due to inhibition of epoxygenase.
2/ concentration during cell swelling could participate
in the activation of these two enzymes during cell Similarly, in Necturus gallbladder, ketoconazole does not
swelling. Along these lines, LTD4 may overcome the inhib- prevent regulatory KCl efflux but stimulates NaCl entry,
itory effect of the calmodulin antagonist pimozide on cell leading to cell swelling (615).
volume regulation, suggesting that LTD4 is a signal down- In addition to their influence on volume-sensitive ion
stream of Ca 2/ (673). channels, phospholipase A2 and a cytochrome P-450 prod-
Arachidonic acid has been shown to inhibit glial cell uct of arachidonic acid have been invoked in mediating
volume regulation (1052) and to inhibit volume regulatory the swelling-induced cellular release of sorbitol (354).
Cl The fatty acid composition of the cell membrane can
0 channels (403, 673, 679, 1047). On the other hand, it
may increase Ca 2/ concentration in renal collecting duct be modulated by dietary polyunsaturated fatty acids,
and activate K which lead to enhanced formation of leukotrienes and
/ channels in neurons (622, 1213). Moreover,
the 15-lipoxygenase product of arachidonic acid thus to acceleration of RVD in Ehrlich ascites tumor cells
(712).
hepoxilin A3 activates volume regulatory K / channels in
platelets (798–801), and the 5-lipoxygenase product LTD4
activates volume regulatory K / and Cl 0 channels (547,
592, 674, 675, 679) and volume regulatory taurine release L. pH in Acidic Cellular Compartments
(592, 678) in Ehrlich ascites tumor cells, as well as taurine
release in fish erythrocytes (1207). 5-Lipoxygenase prod- As evidenced from acridine orange and fluorescein
ucts similarly appear to mediate regulatory cell volume isothiocyanate-dextran fluorescence, hepatocyte swelling
decrease in colonic epithelium (277, 281, 282), chromaffin leads to alkalinization of acidic cellular compartments,
cells (287), MDCK cells (947), and human fibroblasts whereas cell shrinkage enhances the acidity in those com-
(808). However, in most of these cell types, the evidence partments (156, 683, 1088, 1089, 1279, 1280).
comes largely from effects of 5-lipoxygenase inhibitors The lysosomal proteases are known to have their pH
such as nordihydroguaiaretic acid (NDGA). In Ehrlich as- optimum in the acidic range, and alkalinization of the
cites tumor cells (679) and proximal renal tubules (Völkl lysosomes is well known to inhibit hepatic proteolysis
and Lang, unpublished observations), on the other hand, (859, 860). Thus the alkalinizing effect on acidic cellular
the inhibitory effect of NDGA was not overcome by the compartments could at least in theory contribute to the
addition of LTD4, pointing to an additional effect of the antiproteolytic action of cell swelling. Along these lines,
drug not related to 5-lipoxygenase inhibition. It may more alkalinization of acidic cellular compartments parallels
directly inhibit the volume regulatory Cl 0 channels (438) the cell swelling and antiproteolytic effect of transforming
or be effective by increasing arachidonic acid concentra- growth factor-b1 on LLC-PK1 cells (752). However, the
tion (1052). contribution of vesicular alkalinization to the antiproteo-
The enhanced formation of leukotrienes in swollen lytic effect of cell swelling remains to be proven. At least
Ehrlich ascites tumor cells parallels a decreased forma- in liver cells, swelling alkalinizes prelysosomal rather than
tion of PGE2, an effect possibly accounting for the inhibi- lysosomal compartments (766, 1090). Moreover, inhibition
tion of Na / channels (679). Those channels are thought of tyrosine kinase by erbstatin interferes with prelyso-
to be stimulated by PGE2 (679). On the other hand, in somal alkalinization but not with inhibition of proteolysis
ciliary epithelial cells, PGE2 was thought to mediate the (S. vom Dahl and D. Häussinger, unpublished observaactivation
of volume regulatory K tions), pointing to some antiproteolytic mechanisms inde-
/ channels during cell
swelling (191). Prostaglandin E2 similarly activates K /
pendent of lysosomal pH.
channels in MDCK cells (1153) and erythrocytes (743). The alkalinization of acidic cellular compartments in
In collecting duct principal cells, inhibition of phos- hepatocytes occurs not only if cell swelling is due to de-
pholipase A2 with quinacrine blunted the activation of crease of extracellular osmolarity but also if cell swelling
volume regulatory Ca 2/ -sensitive K / channels, which, on is caused by inhibition of K / channels and by concentra-
the other hand, were activated by arachidonic acid (751). tive uptake of amino acids (1279).
In LLC-PK1 cells, however, volume regulatory rubidium It appears that the influence of cell volume on pH of
flux was not modified by arachidonic acid, even though acidic cellular compartments is not confined to prelyso-
it was inhibited by an arachidonic acid antagonist (262). somes in hepatocytes but involves a number of distinct
Ketoconazole, an inhibitor of epoxygenase (cyto- compartments in a great variety of cells, such as pancrechrome
P-450), impedes volume regulatory efflux of os- atic b-cells, glial cells, neurons, vascular smooth muscle
molytes, such as sorbitol, betaine, myo-inositol, or amino cells, proximal renal tubules, MDCK cells, alveolar cells,
acids from renal papillary cells (354), MDCK cells (38), macrophages, and fibroblasts (153–157, 684, 1090, 1283).
and C6 glioma cells (818, 1171). However, the inhibitory Accordingly, the functions of these compartments may be
effect is not reversed by addition of hydroxyeicosatetrae- modified by alterations of cell volume.
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January 1998 FUNCTIONAL SIGNIFICANCE OF CELL VOLUME 259
TABLE 1. Effect of cell volume on gene expression osmotic equilibrium and cell volume constancy (144).
Moreover, cell shrinkage stimulates the expression of heat
Effect Gene/Gene Product Affected
shock proteins that serve to stabilize the proteins and
/
/
/
Cell swelling
c-jun in hepatocytes (328)
c-fos in cardiac myocytes (1044)
JNK-1 in cardiac myocytes (1044)
thus to counteract the detrimental effects of increased
salt concentrations. The cell volume regulated kinase h-
sgk (see sect. IIIH) is a putative element of the signaling
cascade triggering cell volume regulation. Furthermore,
/
/
ERK-1,2 in cardiac myocytes (1044)
Ornithine decarboxylase in LLC-PK1 cells (75, 769),
leukemia cells (977), CHO cells (761), and
cell shrinkage stimulates the expression of proteins with
diverse functions not obviously related to RVI, such as P-
glycoprotein, ClC-K1, and Na / -K / 0
hepatocytes (1215)
TNF-a in macrophages (1392)
-ATPase a1-subunit,
cyclooxygenase-2, the GTPase-activating protein for Rac
/
/
b-Actin (1202)
Tubulin (511)
a1-chimerin, the immediate early gene transcription factors
Egr1–1 and c-Fos, vasopressin, phosphoenolpyruvate
/
/
Cell shrinkage
Aldose reductase in MDCK cells and kidney medulla
(373, 1130)
Na
carboxykinase, tyrosine aminotransferase, tyrosine hydroxylase,
dopamine b-hydroxylase, matrix metalloproteinase
9, and several matrix proteins (see Table 1).
Cell swelling similarly stimulates the expression of a
/ /
-inositol cotransporter SMIT (141, 670, 1318)
Na / -betaine cotransporter BGLT1 (319, 878, 1319, variety of proteins including b-actin, tubulin, cyclooxy-
/
1372, 1393)
Na
genase-2, extracellular signal-regulated kinases ERK-1 and
/ /
/
-taurine cotransporter (1238, 1239, 1320, 1322)
ROSIT, putative osmolyte transporter (1323)
Amino acid transport system A (182, 380, 1135,
ERK-2, JNK, the transcription factors c-Jun and c-Fos,
ornithine decarboxylase, and tissue plasminogen activator
/
1373)
a1-Subunit Na
(see Table 1).
/ -K / /
/
/
-ATPase (322)
P-glycoprotein (1333)
ClC-K1 in kidney (1241)
Serine/threonine kinase h-sgk (1295)
Information on the mechanisms triggering altered
gene expression remains scanty (1254). Some evidence
points to involvement of the cytoskeleton (76). The ex-
/
/
/
Egr-1 in MDCK cells (205, 206, 208) and
cardiomyocytes (1361)
a1-Chimerin in neurons (286)
c-fos in MDCK cells (208), hypothalamic cells (396),
pression of aldose reductase is regulated by a distinct
osmolarity-responsive element (320, 321, 1036). The stimulation
of c-fos expression by swelling of cardiac myoand
cardiomyocytes (1361) cytes is apparently secondary to tyrosine phosphorylation
/
/
/
0
Heat shock proteins (11, 208, 1116, 1192)
Cyclooxygenase-2 (1391)
PEPCK (713, 886, 1317)
Tyrosine hydroxylase in PC12 cells (621)
(1044); the c-jun transcription after swelling of hepatocytes
is at least partially the result of MAPK activation,
followed by phosphorylation of c-Jun (895, 1072, 1211).
0
/
/
Dopamine b-hydroxylase in PC12 cells (621)
Tyrosine aminotransferase (1317)
Tissue plasminogen activator in endothelial and
HeLa cells (733)
Cell volume changes modify phosphorylation of a histonelike
nuclear protein (1057), and hypertonicity has
been shown to alter the karyotype (1237).
/ ab-Crystallin in lens and kidney (245) In mice, a gene (rol) has been identified that renders
0
/
0
Matrix metalloproteinase 9 (1031)
Matrix proteins in chondrocytes (1244)
Laminin B2 in mesangial cells (603)
erythrocytes resistant to osmotic lysis. The product of
this gene is likely to be involved in the stimulation of
volume regulatory K / / Vasopressin (866)
fluxes. However, the precise func-
/ CD9 antigen in MDCK and PAP-HT25 cells (1115) tion of this gene remains elusive (318).
/, Stimulation; 0, inhibition; CHO, Chinese hamster ovary; TNF-a,
tumor necrosis factor-a; MDCK, Madin-Darby canine kidney; PEPCK,
phosphoenolpyruvate carboxykinase. For review, see Reference 144. IV. CHALLENGES OF CELL
Reference numbers are given in parentheses. VOLUME CONSTANCY
M. Gene Expression
A multitude of mechanisms alter cell volume. They
may do so by overriding the volume regulatory mechanims,
by knocking them out, or by shifting their volume
Both cell swelling and cell shrinkage markedly influence
the expression of a wide variety of genes (see Table 1).
regulatory set point.
As indicated in section IIC, exposure of cells to enhanced
extracellular osmolarity or ionic strength stimulates
the expression of aldose reductase and the Na
A. Alterations of Extracellular Osmolarity
/ -
coupled transport systems for inositol, betaine, taurine, In mammalian tissues, most cells are exposed to ex-
and amino acids. The function of these proteins serves tracellular fluid with well-controlled osmolarity. A notable
cellular accumulation of osmolytes and thus reestablishes exception is the kidney medulla, where extracellular os-
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260
LANG ET AL. Volume 78
molarity may approach values exceeding isotonicity by a 858, 1142). Causes include excessive sweating, osmotic
factor of ú4 (1033). Any blood cell passing the kidney diuresis, lack of ADH or defective renal response to ADH,
medulla experiences exposure to this high ambient osmo- and drinking of seawater (553).
larity and subsequent return to isosmolarity within sec- Even though extracellular osmolarity increases due
onds. Medullary cells have not only to cope with this to accumulation of urea in uremia (803), urea easily pasexcessive
extracellular osmolarity for prolonged periods ses cell membranes and does thus not usually cause os-
but encounter rapid changes of osmolarity during transi- motic gradients across the cell membrane. Nevertheless,
tion from antidiuresis to diuresis, when medullary osmo- as shown in several cell types, high extracellular urea
larity rapidly decreases toward isosmolarity (63). concentrations may trigger cell shrinkage by modifying
Less dramatic alterations of extracellular osmolarity the set point for volume regulatory mechanisms (see sect.
occur during intestinal absorption, which exposes intesti- IIIA). Cell shrinkage may be the signal for increase of
nal cells to anisosmotic luminal fluid and may modify osmolyte concentration in the brain, which has been ob-
portal blood osmolarity and liver cell volume (460). served to parallel enhanced urea concentration in uremia
Other tissues are exposed to altered extracellular os- (1223).
molarity during a variety of disorders. Although moderate, Rapid correction of chronically enhanced osmolarity
these alterations are still highly relevant challenges to cell may lead to cell swelling, namely, to cerebral edema (28,
volume control. 1157). Chronic increases of extracellular osmolarity are
Because Na compensated by cells through accumulation of osmolytes,
/ salts (mainly NaCl) contribute ú90% to
extracellular osmolarity, a significant decrease of extra- which may not be rapidly readjusted. Cerebral betaine,
cellular osmolarity is necessarily paralleled by hypona- inositol, and glycerophosphorylcholine, for instance, may
tremia. A variety of clinical conditions can lead to hypona- remain enhanced for days after correction of extracellular
tremia (20, 21, 90, 816, 905, 1265). Hyponatremia may re- hypertonicity (746, 1208). Conversely, rapid correction of
flect an excess of water, either due to excessive oral load
or due to impaired renal elimination, or a deficit of Na
hyponatremia may prove similarly harmful (1141, 1156).
/
due to renal or extrarenal loss (90, 606, 1264). In both
cases, the hyponatremia reflects a decreased extracellular
osmolarity, leading to cell swelling. Excessive water in-
B. Alterations of Extracellular Ion Composition
take is seen in psychiatric disorders (22). Causes for im- Even at constant extracellular osmolarity, cell vol-
paired renal water elimination include inappropriate antiume constancy may be challenged by altered extracellular
diuretic hormone (ADH) secretion, glucocorticoid defi- ion composition (see Table 2).
Most importantly, an increase of extracellular K / ciency, hypothyroidism, and renal and hepatic failure.
con-
Renal and/or extrarenal loss of Na / may result from min- centration depolarizes the cell membrane and eventually
leads to cellular uptake of K / eralocorticoid deficiency, salt losing kidney, nephrotic
with accompanying anions
syndrome, osmotic diuresis, vomiting, and diarrhea (90). (mainly Cl 0 and HCO 0 3 ) and subsequent cell swelling. Con-
versely, a decrease of extracellular K / Moreover, a wide variety of drugs including diuretics,
could result in cell
cyclooxygenase inhibitors, and certain central nervous shrinkage due to cellular loss of KCl (see Table 2).
An increase of extracellular HCO 0 system active drugs may lead to hyponatremia due to
3 concentration
loss of Na / and/or to retention of water (90). Hyposmolar could swell cells by electrogenic entry, hyperpolarization,
reduced driving force for K / hyponatremia is further observed after burns, pancreati-
exit, and subsequent accumutis,
and crush syndrome (90). lation of KHCO3 (976). During correction of extracellular
Hyponatremia does not necessarily indicate hypos- acidosis in the course of the treatment of diabetic ketoacimolarity
but may occur in isosmolar or even hyperosmolar dosis, increasing extracellular pH allows the cells to extrude
H / through the Na / /H / states (90). Extracellular osmolarity may be enhanced de-
exchanger, similarly leading
spite normal or even decreased extracellular Na / concen- to cell swelling (1255).
tration during hyperglycemia in uncontrolled diabetes Several organic anions such as acetate, lactate, and
mellitus (27) and ethanol poisoning (1010). Moreover, hy- proprionate swell cells by entry of the unionized acid,
intracellular dissociation, stimulation of Na / /H / ponatremia cannot be equated with cell swelling. As de-
exchange
tailed in section IVF, cell swelling or cell shrinkage may by cytosolic acidosis, and subsequent accumulation of
Na / prevail in diabetes mellitus. Burns, pancreatitis, and se- and organic anions (see Table 2). A similar effect is
vere trauma, all conditions associated with hyponatremia exerted by CO2. In general, acidosis favors cell swelling,
(see above), may actually lead to muscle cell shrinkage whereas cellular alkalosis has the opposite effect (see
rather than cell swelling (507). Table 2). Along these lines, the cellular accumulation of
Extracellular osmolarity is increased in hyperna- lactate in muscle exercise triggers volume regulatory
tremia, due to excessive oral intake and/or renal retention mechanisms (1048).
Isotonic replacement of Cl 0 of Na with gluconate leads to
/ and/or renal and extrarenal loss of water (325, 553,
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January 1998 FUNCTIONAL SIGNIFICANCE OF CELL VOLUME 261
cell shrinkage due to cellular loss of Cl 0 (and K / ) (see An increase of cell volume appears to be required for cell
Table 2).
proliferation (see sect. VI).
Activation of Na / channels or nonselective cation
channels by excitatory neurotransmitters such as gluta-
C. Energy Depletion mate tends to swell neurons, whereas activation of K /
As pointed out in section IIB, the maintenance of a
channels or anion channels by inhibitory neurotransmitters
such as GABA tends to shrink neurons (see Table 2).
constant cell volume requires the expenditure of energy Secretagogues may stimulate transepithelial trans-
to fuel the Na port by enhancing cellular ion entry, ion exit, or both. If
/ -K / -ATPase, which is required to establish
the ionic gradients across the cell membrane. Inhibition of stimulation of ion entry prevails, the cells swell, whereas
Na if ion exit is preferentially activated, the cells shrink. Thus
/ -K / -ATPase by ouabain or during ischemia eventually
leads to cell swelling. In cardiac myocytes, the swelling secretagogues may either swell (e.g., epinephrine) or
is preceded by transient cell shrinkage due to increase of shrink (e.g., acetylcholine) the cells (see Table 2).
intracellular Ca 2/ and hypercontraction (31, 174, 1131). In kidney medulla, ADH enhances extracellular os-
As would be expected, ischemia leads to swelling of molarity and thus forces the medullary cells to accumu-
the brain (347, 1229) by impairment of Na / -K / -ATPase and late osmolytes (1033, 1075). Furthermore, ADH may more
subsequent accumulation of NaCl (347, 593). However, ac- directly trigger the formation or accumulation of osmocording
to in vitro studies on glial and neuronal cells, energy
depletion alone does not result in cell swelling (35,
lytes (880).
613, 775, 1396). Rather, additional factors such as the intracellular
acidosis (91, 578, 611, 1299) may account for cell
E. Substrate Transport
swelling observed during ischemia (625). Furthermore, cell
swelling in cerebral ischemia is favored by an increase of
The transport and cellular accumulation of amino
acids lead to cell swelling (Table 2). Especially Na / extracellular K
-cou-
/ concentration (612) and by extracellular
accumulation of glutamate (42, 1396), which stimulates cationic
channels through N-methyl-D-aspartate (NMDA) re-
pled transport processes can generate large chemical gradients
across the cell membrane, due to the steep electrochemical
gradient for Na / ceptors and leads to subsequent accumulation of Na
. For instance, cellular gluta-
/ , depolarization,
and uptake of Cl
mine has been observed to increase by ú30 mM after the
0 (185, 186). In the heart,
recovery from ischemia is facilitated in the presence of the
Na
addition of 3 mM glutamine to portal blood (502).
As listed in Table 2, transport of several other sub-
/ /H / exchange inhibitor 3-methylsulfonyl-4-piperidinobenzoyl-guanidine-mesilate
(HOE-694) (1085).
strates such as glucose, taurine, and taurocholeate simi-
larly increases cell volume.
Alterations of cell volume are encountered during
cryopreservation of organs (366, 394, 681). Low temperatures
inhibit the Na / -K / -ATPase and may thus be ex- F. Metabolism
pected to eventually result in cell swelling.
In theory, any reaction resulting in an increase of
osmotically active substances, such as degradation of pro-
D. Ion Transport Altered by Hormones teins to amino acids, glycogen to glucose phosphate, or
and Transmitters triglycerides to glycerol and fatty acids, may be expected
As listed in Table 2, a wide variety of hormones has
to create intracellular osmolarity. However, very little is
known about the influence of metabolism on cell volume.
been shown to alter cell volume. Exercising muscle may lead to cellular accumulation
Most importantly, insulin swells hepatocytes by acti- of lactate and thus may increase cell volume (1048). The
vation of both Na / /H / exchange and Na / -K / -2Cl 0 cotrans- developing intracellular acidosis may compound cell
swelling by activation of the Na / /H / port (4, 472, 953), and glucagon shrinks hepatocytes, pre-
exchanger.
sumably by activation of ion channels (473, 1286, 1287). Diabetic ketoacidosis may cause cell swelling (125,
The effect of these hormones on cell volume accounts for 197, 646, 1388) due to cellular uptake of acids and en-
several of the effects on hepatocyte metabolism (504, 506, hanced Na / /H / exchange activity in compensation for cel-
lular H / 1286, 1287). It should be pointed out that insulin and glu- generation (1255). More importantly, high glucose
cagon modify cell volume at hormone concentrations well concentrations favor cellular formation and accumulation
encountered under physiological conditions. This is not of sorbitol through aldose reductase (143, 180, 559, 748,
necessarily true for all hormones listed in Table 2. Similar 990, 1196). As a consequence, cells decrease other osmo-
to insulin, several growth factors increase cell volume in lytes such as myo-inositol (143, 411, 1079, 1158, 1222,
a variety of cells by stimulation of Na / /H / exchange and 1386, 1387), an effect which can be reversed by inhibition
in some cases of Na of aldose reductase with sorbinil (303, 326, 1218). On the
/ -K / -2Cl 0 cotransport (see Table 2).
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262
TABLE 2. Factors altering cell volume
LANG ET AL. Volume 78
Factor Cell Affected Factor Cell Affected
Factors leading to cell swelling Factors leading to cell swelling—Continued
Insulin Hepatocytes (4, 472, 473, 953, 1287, 1286),
pneumocytes (805)
IGF-I Hepatocytes (1285)
Growth hormone Chondrocytes (557)
ADH (AVP) Glial cells (259, 705)
Glucocorticoids Hepatocytes (660)
Fibroblasts (316)
Mineralocorticoids Leukocytes (1329–1331)
Estrogens Astrocytes (344)
Parathyroid glands (137)
Progesterone Astrocytes (344)
Parathyroid glands (137)
Testosterone Parathyroid glands (137)
Gonadotropin Leydig cells (1346)
Somatostatin Colon cells (277)
Adenosine Erythrocytes (1132)
Angiotensin Vascular smooth muscle cells (296)
Interleukin Lymphocytes (1184)
a-Adrenergic Hepatocytes (1286)
b-Adrenergic Erythrocytes (56, 323, 459, 862)
Salivary glands (172)
Sweat glands (907)
Acetylcholine* Sweat glands (907)
Myogenic L6 cells (1110)
Glutamate* Glial cells (73, 185, 486–488, 594, 1084,
1151)
Neurons (185, 186, 975, 1059)
Kainate Neurons (24, 999)
NMDA Brain (190, 1267)
Aspartate Neurons (1059)
Deoxyadenosine Lymphoblastoid cells (36)
cAMP Sweat glands (907)
cGMP Barnacle muscle (957)
PKC-e,d Promyelocytes (1302)
Arachidonic acid Glial cells (1147, 1148)
ras Oncogene Fibroblasts (695, 824)
Phorbol esters Necturus gallbladder (247)
Genistein Tumor cells (925)
Okadaic acid Erythrocytes (581, 597, 941)
Superoxide Erythrocytes (1247)
Lithium Erythrocytes (935, 944)
Magnesium Erythrocytes (332, 943, 944)
Amino acid uptake Hepatocytes (43, 51, 60, 204, 342, 471,
502, 653, 654, 1300, 1341)
Proximal renal tubule (67, 69, 122, 173)
Intestine cells (706, 785, 788, 930, 1092,
1095)
Glucose uptake Necturus gallbladder (355)
Kidney (67)
LLC-PK1 cells (75)
Intestine cells (785)
Vascular smooth muscle cells (881)
Mesangial cells (620)
Bile acids Hepatocytes (497, 506)
Increase of K /
Hepatocytes (1261)
Gallbladder epithelium (229, 528, 639)
Proximal renal tubule (261, 631, 689,
1282)
Renal cortical slices (973)
Thick ascending limb (1178)
Amphiuma diluting segment (443)
Shark rectal gland (638)
Glial cells (46, 259, 594, 612, 628, 731, 802,
847, 902, 1086)
Neurons (24, 33, 1086)
Retinal Müller cells (312)
GH-producing cells (307)
Adrenal glomerulosa cells (513)
Vestibular dark cells (1314)
Ba 2/ , quinidine* Proximal renal tubule (1174, 1282)
Hepatocytes (12, 498, 618)
A6 cells (272a)
MDCK cells (1176)
Ouabain* Necturus gallbladder (251, 378)
Thick ascending limb (1179)
Collecting duct principal cells (1164,
1165)
Neurons (168)
Platelets (806)
Enterocytes (784)
Sperm (258)
HCO 0 3
Parotid glands (976)
Acidosis Proximal renal tubule (1174, 1175)
Neurons (1149, 1150)
Glial cells (611, 883, 1145, 1146, 1149,
1151, 1172)
Esophageal cells (1214)
(Short chain) Enterocytes (278, 280, 1032)
fatty acids* Proximal renal tubule (1016)
Erythrocytes (385)
Brain (178)
Vestibular dark cells (1313)
NH 3
Shark rectal gland (315)
Astrocytes (867, 897, 898)
Opossum kidney cells (982)
Cytochalasin B Lymphoblast cells (36)
Colchicine Lymphoblast cells (36)
Vinblastine* Lymphoblast cells (36)
Endotoxin Hepatocytes (127)
N-methylformamide HT-29 cells (260)
Chlorpromazine* Erythrocytes (219, 1205)
Hydroxyurea Endothelial cells (2)
Ethanol Hepatocytes (1362)
Adenohypophysial cells (1063)
Cardiac cells (552)
Proximal tubule cells (600)
Dideoxycytidine Monoblastoid cells (115)
Mercurials MDCK cells (1028)
Shark rectal gland (637)
Dioxin* Hepatocytes (1344)
Veratridine Neurons (190)
Hyperthermia Chondrocytes (335)
Osteoblasts (335)
Hemolysin Erythrocytes (556)
Photofrin Tumor cells (729, 730)
Fertilization Sperm (1212)
Electric field Outer hair cells (906)
stimulus
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January 1998 FUNCTIONAL SIGNIFICANCE OF CELL VOLUME 263
TABLE 2—Continued
Factor Cell Affected Factor Cell Affected
Factors leading to cell shrinkage Factors leading to cell shrinkage—Continued
Glucagon Hepatocytes (379, 473, 1287)
VIP Intestine (276, 901, 1297)
Somatoliberin GH-producing cells (307)
(hGHRH)
ADH MDCK cells (1176)
Hepatocytes (1286)
Atriopeptin (ANF) glial cells (705)
Cardiac myocytes (198, 199, 201)
NO Heart (200, 201)
ATP Endothelial cells (916)
Hepatocytes (1286)
Bradykinin Enterocytes (1210)
Fibroblasts (1005)
Ehrlich cells (547, 1126)
Endothelial cells (916)
Histamine Enterocytes (1210)
Ehrlich cells (547)
Thrombin Enterocytes (1210)
Ehrlich cells (547, 1126)
Serotonin Leech glial cells (46)
Adenosine Renal collecting duct (1107)
Hepatocytes (1286)
fMLP Granulocytes (955)
Corticostatic Enterocytes (786)
peptides
a-Adrenergic Hepatocytes (849)
Salivary glands (797)
Isoprenaline Nonpigmented ciliary epithelium (183)
Acetylcholine* Salivary glands (338, 341, 699, 797, 846,
872, 873, 882, 911, 976, 1363)
Sweat glands (1181, 1189)
Enterocytes (1210, 1297)
Erythrocytes (743)
PGE 2
H 2O 2
Hepatocytes (470, 1045)
cAMP Necturus gallbladder (229, 994)
Hepatocytes (1286)
MDCK cells (828, 829, 833, 1176)
Barnacle muscle (957, 987)
Pulmonary epithelium (787)
Pancreatic epithelial cells (1182)
Pancreatic epithelium (643)
Intestine (1251)
Nonpigmented ciliary epithelium (183)
cGMP Heart (199, 201)
A23187* Pulmonary epithelium (787)
Enterocytes (786, 1210)
Erythrocytes (134, 310)
Fibroblasts (1358)
Neuroblastoma cells (233)
Thapsigargin Enterocytes (786)
Okadaic acid* Hepatocytes (101)
Cytochalasin B MDCK cells (828, 829)
Colchicine Macrophages (821)
Ouabain Neurons (16)
Cardiac myocytes (1131)
Vascular smooth muscle cells (919)
Decrease in K / o
Removal of Na / o
Removal of Cl 0 o
Removal of Ca 2/
o
Proximal renal tubules (631)
Erythrocytes (291)
Leech glial cells (46)
Pigmented ciliary epithelium (301)
Muscle cells (959)
Pigmented ciliary epithelium (301)
Kidney (777)
Pigmented ciliary epithelium (301)
Toad bladder (740)
Amphibian skin (434, 1246)
Erythrocytes (933, 939)
Muscle cells (958)
Mg 2/ depletion Erythrocytes (711)
Starvation Hepatocytes (3, 1140)
Heme oxygenation Erythrocytes (163, 164)
Elastin peptides Tumor cells (946)
Urea Proximal renal tubules (359)
Hepatocytes (474)
Erythrocytes (936)
Mastoparan MDCK cells (1350)
NDS Enterocytes (790)
Furosemide* Macula densa cells (964)
MDCK cells (1176)
MAG-3but HL-60 leukemic cells (162)
Ethanol Prolactin-secreting cells (1063, 1068)
Thyrotropin-releasing cells (1063)
Amphotericin B Cornea epithelium (992)
Macrophages (299)
Lead Erythrocytes (310)
Cisplatin Renal tubule cells (110)
Noise Auditory hair cells (275)
VIP, vasoactive intestinal polypeptide; NDS, neutrophil-derived secretagogue; MAG-3but, monoacetone glucose 3-butyrate; NMDA, N-methyl-Daspartate;
IGF-I, insulin-like growth factor I; ADH, antidiuretic hormone; AVP, arginine vasopressin; PKC, protein kinase C; ANF, atrial natriuretic
factor; NO, nitric oxide; PG, prostaglandin; fMLP, formyl-methionyl-leucyl-phenylalanine; hGHRH, human growth hormone-releasing hormone. * Or
similarly active drugs. Reference numbers are given in parentheses.
other hand, hyperglycemia is paralleled by hyperosmolar- explored. On the other hand, the cellular formation of perity,
which shrinks cells. In fact, some evidence points to oxides has been shown to shrink hepatocytes due to activa-
shrinkage of polymorphonuclear lymphocytes in hyperos- tion of K / channels at the cell membrane (1045). Peroxides
similarly activate K / molar diabetes mellitus (269).
channels in pancreatic b-cells (652)
In addition to creating osmotically active substances, and vascular smooth muscle cells (651) but inhibit N-type
metabolic pathways may alter cell volume indirectly K / channels in lymphocytes (1183) and minK channels
through modification of transport processes across the cell (152), which are expressed in a variety of cells (150). In
membrane. For instance, a decrease of cellular ATP could endothelial cells, peroxides inhibit Na / -K / -2Cl 0 cotransport
activate ATP-sensitive K (305). However, the consequences on cell volume have not
/ channels and thus shrink susceptible
cells, a possibility which has, however, not yet been been tested in any of those cells.
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264
G. Others
In addition to hormones, a great number of drugs and
toxins lead to cell swelling or cell shrinkage (Table 2).
For most substances, the functional significance of the
effect on cell volume has not been explored.
In several stress situations, such as surgical intervention
(306), acute pancreatitis (1027), severe injury, burns,
and sepsis (79), a decrease of muscle intracellular space
has been observed, leading to disinhibition of proteolysis
and thus to hypercatabolism (507). However, the mechanisms
underlying muscle cell shrinkage have not yet been
elucidated.
V. ROLE OF CELL VOLUME REGULATORY
MECHANISMS IN CELL FUNCTIONS
A. Erythrocyte Function
Erythrocyte volume and shape are important determinants
of blood viscosity. Cell volume regulatory mechanisms
are specifically important in limiting alterations of
cell volume during their passage through the hypertonic
kidney medulla and during HCO 0 3 transport in the lung
and the periphery. One disorder exacerbated by altered
LANG ET AL. Volume 78
erythrocyte cell volume regulatory mechanisms is sickle
cell anemia, where mutations of the hemoglobin chain
FIG. 1. Three examples illustrating role of cell volume in coupling
of apical to basolateral cell membranes in epithelia. A: Na / (HbS) favor the polymerization of deoxygenated hemoglo-
-coupled
transport across apical cell membrane of proximal renal tubules leads
to accumulation of Na / bin, leading to characteristic changes of cell shape (sick-
and substrate [e.g., amino acids (AA)] and thus
to cell swelling, which activates basolateral K / ling) and impaired deformability of the erythrocytes (591,
channels. B: electrolyte
uptake by Na / -K / -2Cl 0 737); the consequence is a severe increase of blood viscoscotransport
across basolateral cell membrane in
dark vestibular cells leads to cell swelling and subsequent activation of
luminal K / channels. C: stimulation of apical Cl 0 channels in Cl 0 ity (591). The polymerization of hemoglobin is highly de-secreting
cells leads to loss of Cl 0 and, because of depolarization, of K / pendent on protein concentration and thus on cell volume
. Cell
shrinkage and decrease of intracellular Cl 0 activity in turn stimulate
(297, 298). In HbS erythrocytes, volume regulatory KCl basolateral Na / -K / -2Cl 0 cotransport.
cotransport (133, 163, 164, 343, 1276) is enhanced, partially
due to direct interaction with the mutated hemoglo-
bin (914). Furthermore, cell shrinkage is presumably fa-
vored by enhanced activity of Ca 2/ -sensitive K / channels
(105, 134, 343) due to increase of intracellular Ca 2/ con-
centration. The ensuing cell shrinkage further favors the
polymerization of hemoglobin (591). The expression of
the Na / /H / exchanger is enhanced, possibly in compensa-
tion for cell shrinkage (165). Similarly, cell volume is decreased
in homozygous hemoglobin C disease (135).
B. Epithelial Transport
Transcellular ion transport in epithelia is accom-
plished by entry mechanisms across one cell membrane
and ion exit mechanisms at the other cell membrane. Obviously,
the entry or extrusion of osmotically active sub-
stances during epithelial transport represents a continu-
In intestine, gallbladder, and renal proximal tubules
(see Fig. 1A), the luminal uptake of substrates for Na / -
coupled transport, such as glucose or amino acids, tends
to swell the cells, leading to volume regulatory activation
of K / channels in the basolateral cell membrane (67, 68,
122, 173, 355, 493, 687, 692, 706, 782, 995, 1092–1096,
1230). The activation of these channels not only limits
cell swelling but maintains the electrical driving force for
continued transport.
In the NaCl-reabsorbing thick ascending limb of
Henle’s loop and diluting segment of the amphibian kid-
ney, NaCl entry is accomplished by luminal Na / -K / -2Cl 0
cotransport, basolateral Cl 0 channels, and Na / -K / -
ATPase as well as apical and basolateral K / channels (416,
900, 1178). Inhibition of Na / -K / -ATPase leads to rapid cell
swelling, which is prevented by inhibition of luminal Na / -
ous challenge to cell volume constancy. K / -2Cl 0 cotransport (444, 520, 1178). On the other hand,
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January 1998 FUNCTIONAL SIGNIFICANCE OF CELL VOLUME 265
stimulation of transport by ADH involves a well-coordi- cytosol by impairment of HCO 0 3 exit (687), whereas os-
nated increase of transport rate across both luminal and motic cell swelling leads to cytosolic acidification (see
basolateral cell membranes (521) without any appreciable sect. IIIE). Because K / channels are highly sensitive to
increase of cell volume (519). If the cells are shrunk by cytosolic pH (692), their activation is expected to be dif-
increased extracellular osmolarity, they do not display ferent between osmotic and substrate-induced cell swelling.
In enterocytes, RVD apparently depends on Ca 2/ RVI unless they are stimulated with ADH or cAMP (520,
from
522, 1177). The hormone not only activates luminal Na / - outside and calmodulin-sensitive K / channels, whereas
K substrate-induced cell swelling appears to be counterreg-
/ -2Cl 0 cotransport but also a Na / /H / exchanger in the
basolateral cell membrane, which contributes to ion accu- ulated by cellular Ca 2/ release and subsequent activation
of Cl 0 mulation during RVI (520, 522, 1177).
channels by protein kinase C (782, 788).
Potassium secretion in dark vestibular cells (see Fig. Volume-mediated activation of transporters not only
1B) and stria vascularis marginal cells of the inner ear involves ion channels and ion transporters. As pointed
is accomplished by basolateral Na / -K / -2Cl 0 cotransport, out above, cell shrinkage stimulates the expression and/
or activity of Na / Na -coupled transporters for inositol (877),
/ -K / -ATPase, and Cl 0 channels as well as apical minK
channels (1311). The K / channels are activated by cell betaine (1242, 1372), taurine (1238), and neutral amino
swelling (1120, 1312), and the basolateral Na acids (182, 380, 1135, 1373). Cell swelling, on the other
/ -K / -2Cl 0 cotransport
by cell shrinkage (1315). Cell volume couples hand, stimulates cellular release of the above osmolytes
the two cell membranes, since excess Na and of glutathione (503) and cellular uptake of alanine
/ -K / -2Cl 0 cotransport
would swell the cells and thus activate the apical and glutamine (502, 1335) and of taurocholate (469, 497).
K Stimulation of osmolyte flux during alterations of cell vol-
/ channels, and excess K / channel activity would shrink
the cell and thus turn on Na / -K / -2Cl 0 cotransport. More- ume serves to regulate cell volume rather than transepi-
over, exposure of the basolateral side to a hypotonic methelial transport, but entry and/or exit may be polarized
dium stimulates transepithelial transport (1312), possibly (377, 480, 630, 1372), and in the liver, cell swelling indeed
by decreasing intracellular Cl stimulates transepithelial transport of taurocholate (469,
0 and subsequent activation
of Na / -K / -2Cl 0 cotransport. 508) and leukotrienes (1340).
In tight epithelia reabsorbing Na / , such as urinary
Hyperosmolarity stimulates urea transport (392, 393)
bladder, Na / entry through luminal Na / channels is simi- but inhibits transport of NaCl in inner medullary collect-
larly coordinated with Na ing duct (410) and salivary gland (874).
/ -K / -ATPase and K / channels
at the basolateral cell membrane (179, 329, 742, 789, 995, Stimulation of transport during cell swelling may be
1232, 1233, 1303, 1349). Accordingly, inhibition of the Na the result of insertion of the carriers and/or channels into
/ -
K / -ATPase in toad urinary bladder leads to parallel inhibi- the cell membrane by exocytosis (114, 132, 462, 497, 912,
tion of luminal Na 969, 1260, 1354). Exocytosis may be stimulated by an in-
/ channels, preventing luminal Na / entry
and cell swelling (252). crease of intracellular Ca 2/ activity. In lung alveolar type
II cells, the increase of intracellular Ca 2/ In several tight epithelia, insertion of Na concentration
/ channels
was stimulated by decrease of extracellular osmolarity due to mechanical stress not only accounts for exocytosis
(1231, 1347), a function obviously serving Na but also for stimulation of surfactant secretion (1354).
/ homeostasis
rather than cell volume regulation. Protein secretion in seminal vesicles, on the other hand,
Activation of K is inhibited by both hyper- and hypotonic extracellular
/ and Cl 0 channels during stimulation
of secretion in several epithelia (Fig. 1C) may lead to cell fluid (554). Exposure of the apical side of the pulmonary
shrinkage due to cellular KCl loss (229, 338, 339, 873, epithelium to hypotonic fluid is thought to stimulate the
1363). Shrinkage then turns on volume regulatory Na / / secretion of a humoral factor, leading to bronchodilation
H (367).
/ exchange and/or Na / -K / -2Cl 0 cotransport, which may
partially recover cell volume and at the same time supply Whether the polarized trafficking of vesicles in epithe
cell with further Cl thelia is influenced by cell volume has not yet been ex-
0 for secretion (341, 549, 796, 797).
Thus, during both reabsorption of Na / and substrates plored. The polarized distribution of secretory proteins is
and secretion of Cl modified by an alkalinization of vesicular pH (167, 931)
0 , cell volume participates in the coupling
of the basolateral and luminal cell membrane, the and could thus theoretically be sensitive to cell volume.
so-called cross-talk between the opposing cell membranes However, the alkalinization of vesicles during cell swell-
(995). It should be kept in mind, however, that cell volume ing may be too small to significantly interfere with traf-
participates in, but does not fully account for, the coupling ficking.
of the cell membranes (687). Accordingly, even though In addition to its effect on transcellular transport, cell
osmotic cell swelling mimics many effects of swelling in- volume has been demonstrated to modify the permeability
duced by substrate transport, the underlying mechanisms of tight junctions and thus paracellular transport. How-
are not necessarily identical. For instance, the depolarizaever, the reported effects are not consistent (29, 111, 402,
tion resulting from Na / -coupled transport alkalinizes the 930, 962, 1348, 1384).
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266
LANG ET AL. Volume 78
TABLE 3. Influence of cell volume on metabolism the cell swelling effect of the hormone. Conversely, glucagon
and cAMP stimulate proteolysis and glycogenolysis
Effect Process Affected
and inhibit protein synthesis in part by cell shrinkage due
/ Glycogen synthesis in hepatocytes (4, 12, 50, 51, 53, 455,
456, 555, 819, 953) and muscle (762)
to activation of ion channels and subsequent release of
KCl (504). Although cell shrinkage correlates well with
0
0
/
Glycogenolysis (406, 696)
Glucose-6-phosphatase activity (409)
Glucokinase activity in hepatocytes (1261)
the inhibitory effect of cAMP and ADH on protein synthesis,
this is not true for the effects of insulin and phenyleph-
0 Glycolysis in muscle and fibroblasts (196, 918) rine (1159). Thus cell volume may play a less prominent
/
/
/
Glycolysis in hepatocytes (953)
Macrophages and lymphocytes (1366)
Lactate uptake in hepatocytes (696)
Pentose phosphate shunt in hepatocytes (496, 1046)
role in hormonal regulation of protein synthesis than in
proteolysis. The same probably holds true for glycogen
metabolism and lipogenesis.
0
/
Release of glutamine and alanine from muscle (945)
Protein synthesis in hepatocytes (1007, 1159), HeLa cells
(1008, 1343), and mammary cells (825)
The antiproteolytic effect of cell swelling depends on
an intact microtubule network (156, 1284) and could thus
0
/
/
Proteolysis in hepatocytes (471, 472, 498, 499, 767, 1284,
1285, 1287)
Amino acid uptake (100, 500, 502)
Glutamine breakdown in liver (502), lymphocytes, and
macrophages (1366)
not be reproduced in freshly isolated hepatocytes (820),
which suffer from a disintegrated microtubule network
(511, 1284).
The set points of volume regulatory mechanisms and
0
/
/
Glutamine synthesis (502)
Glycine and alanine oxidation (496, 510, 676)
Urea synthesis from amino acids (505)
thus cell volume can be altered by a wide variety of other
hormones and transmitters, which thus trigger the meta-
0 Urea synthesis from NH / 4 (500, 502) bolic pattern typical for swollen or shrunken cells (Table
/
0
/
Glutathione (GSH) efflux (503)
GSSG release into bile (1046)
Ornithine decarboxylase activity and expression (769,
1). By this means, the mediators exploit volume regulatory
mechanisms to exert their effects on cellular metabolism.
1215) In addition to hormones, nutrients may modify pro-
/
/
/
RNA and DNA synthesis in HeLa cells (1008)
Ketoisocaproate oxidation (510)
Acetyl CoA carboxylase (49, 51, 53, 555)
tein, glycogen, and lipid metabolism in part through their
influence on cell volume. In fact, the antiproteolytic effect
/ Lipogenesis (51) of glutamine and glycine in liver has been shown to be
0
/
/
Carnitine palmitoyltransferase I activity (457, 841, 1389)
Taurocholate excretion into bile (469, 497, 508)
Respiration in glial cells (609) and sperm (231)
completely accounted for by their influence on cell volume
(471). The antiproteolytic and swelling effect of gly-
0
0
/
Cellular ATP concentration in hepatocytes (820)
Phosphocreatine concentrations in glioma cells (747)
Formation of active oxygen species in neutrophils (658,
659)
cine is potentiated after starvation (471, 1285), which
upregulates the glycine transporting system A (515). However,
the antiproteolytic action of other amino acids such
/ Bile secretion (497) as phenylalanine, serine, alanine, and proline cannot be
/, Stimulation upon cell swelling and/or inhibition by cell shrinkage;
0, inhibition upon cell swelling and/or stimulation by cell shrinkage.
For effects on gene expression, see Table 1. For effects on intracellular
fully explained by their effects on cell volume. Thus mechanisms
other than cell swelling contribute to the antiproteolytic
action of some amino acids.
signaling, see text. Reference numbers are given in parentheses. The influence of cell volume on metabolism is not
restricted to macromolecular synthesis and breakdown.
C. Regulation of Metabolism
Swelling of hepatocytes apparently interferes with the
transfer of reducing equivalents through the mitochondrial
malate/aspartate shuttle (503). The lack of aspartate
As listed in Table 3, cell volume changes modify a impedes the formation of urea from NH3, an effect that
wide variety of metabolic functions. Most importantly, is overcome by addition of lactate and pyruvate, allowing
cell swelling favors the synthesis and inhibits the degrada- the mitochondrial regeneration of oxaloacetate (503). The
tion of proteins, glycogen, and to a lesser extent lipids formation of urea from glutamine is enhanced after cell
(504, 506). Cell shrinkage has the opposite effect. Thus swelling (500).
cell swelling can be considered as an anabolic signal, Some effects of cell swelling caused by a decrease
whereas cell shrinkage favors cell catabolism.
of extracellular osmolarity may actually be due to con-
In hepatocytes, the influence of cell volume on metab- comitant mitochondrial swelling (969) because of de-
olism is one way that insulin and glucagon exert their creasing ambient osmolarity. Glutamine breakdown (502)
metabolic effects. Insulin increases liver cell volume by and glycine oxidation (510), for instance, are stimulated
activation of Na not only by decrease of extracellular osmolarity but also
/ /H / exchange and Na / -K / -2Cl 0 cotransport
and thus triggers a variety of metabolic functions, by glucagon, cAMP, and several Ca 2/ -mobilizing hor-
including protein and glycogen synthesis and inhibition mones that swell mitochondria (465–467), but at the same
of protein and glycogen degradation (4, 504, 506). The time shrink hepatocytes (see Table 2). Similarly, the
effect of insulin on proteolysis is fully accounted for by swelling-induced decrease of the b-hydroxybutyrate-to-
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January 1998 FUNCTIONAL SIGNIFICANCE OF CELL VOLUME 267
acetoacetate ratio (510) is probably due to stimulation of (246, 485, 531, 644, 909) and K / depletion (485, 700, 701),
the respiratory chain due to concomitant mitochondrial both maneuvers expected to shrink cells. Conversely, in-
swelling (274, 466). ternalization of LDL or ferritin is increased by hypotonic
Peroxides may modify cell volume by activation of extracellular fluid (644, 707). However, because almost
ion channels (see Table 2). They shrink hepatocytes by identical effects were exerted by KCl and NaCl but not
activation of K by glucose or urea, the altered internalization appeared
/ channels (470). On the other hand, superoxide
has been shown to swell erythrocytes (1247). Cell to be due to the ionic strength rather than cell volume
volume in turn influences the peroxide metabolism; cell (644). Increased ionic strength may impede internalization
swelling stimulates and cell shrinkage inhibits flux by interference with the formation of coated pits (531).
through the pentose phosphate pathway and NADPH gen- On the other hand, cell swelling has been shown to inhibit
eration (1046). Thus cell swelling provides NADPH for endocytosis (1316).
glutathione reductase to produce reduced glutathione Cell swelling leads rather to cytosolic acidification
(GSH) and strengthens the protective mechanisms against (see sect. IIIE), which has been shown to interfere with
peroxides (1046). On the other hand, cell swelling should endocytosis from coated pits (485, 530, 1056). Moreover,
favor the formation of reactive oxygen species by NADPH cell swelling reverses lysosomal acidification, which is a
oxidase, which is inhibited by high osmolarity (1186). Fur- prerequisite for normal recycling of LDL (57) and transthermore,
components of the cytosolic burst oxidase have ferrin receptors (248). Accordingly, cell swelling would
been found to be dissociated by high osmolarity (573). have been expected to impede receptor recycling. The
Moreover, cell swelling stimulates formation of arachi- vesicular alkalinization and cytosolic acidification after
donic acid (see sect. IIIK), which is required for activation cell swelling may not be sufficient to significantly interfere
of NADPH oxidase (526). Accordingly, osmotic cell swell- with receptor recycling, and the effects of ionic strength
ing stimulates (602) and osmotic cell shrinkage inhibits exceed the weak effects of cell volume. The reason for
formation of peroxides in neutrophils (602, 659, 795, 810). the interference of K / depletion with the formation of
The enhanced formation of sorbitol in diabetes melli- coated pits (701) remains, however, unexplained.
tus (see sect. IVF) has been implicated in the generation In glial cells, NH3, which swells the cells (10, 897,
of several diabetic complications such as neuropathy, reti- 898) and alkalinizes their lysosomes (153), leads to upregnopathy,
microangiopathy, and cataracts (143). Similarly, ulation of peripheral type benzodiazepine receptors (571,
the cellular accumulation of galactitol with subsequent 572). Moreover, binding of benzodiazepine to glial cells
decrease of other osmolytes has been implicated in the (570), muscarinic drugs to peritoneal cells (537), atrial
pathophysiology of galactosemia (80, 302). However, the natriuretic peptide to collecting duct cells (561), and en-
mechanisms linking cell swelling with defined sequelae of dothelin to renal cells (1268) increases after hypotonic
diabetes mellitus or galactosemia are far from under- exposure. Excessive osmotic shrinkage, on the other
stood. hand, has been shown to induce clustering and internal-
Information on metabolic effects of cell volume in ization of cytokine receptors and thus to mimic effects of
mammalian cells other than hepatocytes is still scarce the ligands (1020).
(see Table 3), even though it appears highly unlikely that Taken together, these data do not suggest a uniform
the influence of altered cell volume on metabolism is re- influence of cell volume as such on the regulation of cell
stricted to hepatocytes. For instance, mechanical or osmotic
deformation of chondrocytes or osteoblasts, re-
membrane receptors.
spectively, may stimulate the synthesis of proteoglycans
and proteins (123, 623, 1244) and thus foster cartilage and
bone growth, which indeed correlated with chondrocyte
E. Hormone and Transmitter Release
volume (661). Moreover, a decrease of muscle cell volume An increase in cell membrane tension, as occurs dur-
was correlated with hypercatabolism in several clinical ing cell swelling, has been described to trigger fusion of
conditions (507). endocytotic vesicles with the plasma membrane, leading
Certainly, more experimental information is needed to release of vesicle contents and insertion of ion channels
on the interaction of cell volume and cell metabolism in in the cell membrane (132, 417, 462, 508, 969, 1260). The
mechanism requires Ca 2/ other cells, such as glial cells and adipocytes.
and an intact actin filament net-
work. If the same is true for secretory vesicles, osmotic
cell swelling should stimulate hormone release (Fig. 2).
D. Receptor Recycling Cell swelling has indeed been shown to trigger the
release of insulin (95, 768), prolactin (414, 1063, 1066,
The formation of coated pits and internalization of 1070, 1304, 1306, 1307, 1309), gonadotropin-releasing horlow-density
lipoproteins (LDL) and transferrin receptors mone (563), luteinizing hormone (414, 415), thyrotropin
are inhibited by both increase of extracellular osmolarity (414, 1065, 1306), aldosterone (514, 1081–1083, 1301), and
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268
LANG ET AL. Volume 78
stance P from C-fiber neurons (375). Alterations of NaCl
concentrations have further been shown to modify transmitter
release from various regions of the brain (551).
Renin secretion is inhibited by an increase of intracellular
Ca 2/ activity, the so-called Ca 2/ paradox of renin
secretion (461, 923). It has been suggested that an increase
of intracellular Ca 2/ activity activates Ca 2/ -sensitive Cl 0
channels, thus leading to cellular loss of KCl and cell
shinkage, which in turn would inhibit renin release (665).
Cell volume may further modify hormone and transmitter
release through pH changes in secretory vesicles.
In pancreatic b-cells, for instance, acidic proteases within
the acidic secretory granules cleave proinsulin to yield
FIG. 2. Mechanism of stimulated hormone release and of contrac- insulin, a function probably compromised by cell swelling
tion after swelling of endocrine and vascular smooth muscle cells, respectively.
Swelling leads to activation of anion channels, and exit of
Cl
and fostered by cell shrinkage. Furthermore, the release
of insulin may be modified by the luminal pH of the secre-
0 depolarizes cell membrane. Subsequent activation of voltage-sensi-
tive Ca tory granules and thus be sensitive to alterations of cell
2/ channels stimulates Ca 2/ entry. Ca 2/ then triggers hormone
release from endocrine cells or contraction of smooth muscle cells, volume. In neurons, metabolism, uptake, and release of
respectively.
neurotransmitters may be modified by the luminal pH of
synaptic vesicles. For instance, the uptake of neurotransmitters
such as catecholamines, glutamate, GABA, and
renin (345, 582, 1128, 1129). Where tested, the hormone- acetylcholine into small synaptic vesicles is driven by a
releasing effect was correlated with an increase of intra- proton gradient between the cytosol and the acid lumen
cellular Ca 2/ activity (514, 983, 1062, 1064–1069, 1080, (254). Uptake of glutamate and aspartate into glial cells
1308). In insulin-secreting b-cells, Ca 2/ entry during cell has indeed been found to be impaired by osmotic cell
swelling is partially due to activation of Cl 0 channels (82), swelling (628).
with subsequent depolarization of the cell membrane and Transmitter metabolism may be further influenced by
opening of voltage-sensitive Ca 2/ channels (124). cell volume through effects on the expression of enzymes.
Osmotic cell shrinkage has been shown to inhibit At enhanced extracellular K / , an increase of extracellular
prolactin release, presumably by inhibiting Ca 2/ influx osmolarity inhibits the expression of tyrosine hydroxylase
(1065, 1305). Furthermore, increase of extracellular osmo- and dopamine b-hydroxylase in PC12 cells (621). Increaslarity
decreases the formation and release of endothelin- ing extracellular osmolarity at low extracellular K / was,
1 (640). however, without effect on the expression of these en-
For atrial natriuretic factor (ANF), the position is less zymes (621).
clear. It is released from cardiac myocytes in response to Some of the osmolytes released during cell swelling
mechanical stretch (198, 1071) and osmotic cell swelling of neurons such as glutamate (148, 304, 523, 550, 865,
(412). Cell volume may be part of a negative-feedback 1339), aspartate (550, 891), GABA (774, 891), glycine
loop limiting ANF release. Atrial natriuretic factor inhibits (891), and taurine (184, 560) function as neurotransmitters
the cardiac Na / /K / /2Cl 0 exchanger via guanosine 3�,5�- in the brain. Hyperosmolar glucose or sorbitol concentracyclic
monophosphate (cGMP), with the resulting cell tions inhibited K / -induced GABA release and inhibited
shrinkage then inhibiting ANF release (199, 201). On the K / -induced release of norepinephrine and serotonin (327).
other hand, ANF release has been postulated to be stimulated
by cell shrinkage (1399, 1400).
In contrast to the above hormones, vasopressin is F. Excitability and Contraction
released during cell shrinkage, which apparently leads to
disinhibition of a stretch-inactivated cation channel. The After swelling of cardiac cells, volume-sensitive Cl 0
activation of this channel leads to depolarization and ac- currents have been shown to depolarize the cell memcelerated
action potentials (913). Interestingly, ethanol, brane (1253, 1394), enhance excitability, and reduce the
which triggers hormone release from other cells (1063, duration of the action potential (1139). On the other hand,
1068), is known to inhibit vasopressin release (90). In moderate osmotic shrinkage exerts a positive inotropic
addition to ADH, the release of nitric oxide (1152) and of effect in the heart (74, 432). This latter effect may be due
the putative hormones ouabain or ouabainlike factors (98, to a direct influence on the contractile elements. As shown
744) may be stimulated by an increase in plasma osmolar- in skinned muscle fibers, increased ionic strength destabi-
ity. Furthermore, hyperosmolarity stimulates the release lizes the actinomyosin complex, thus interfering with the
Ca 2/ of histamine from basophil granulocytes (892) and of sub- -activated force (41, 398). To the extent that cell
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January 1998 FUNCTIONAL SIGNIFICANCE OF CELL VOLUME 269
shrinkage leads to increase of intracellular ionic strength,
this effect could modify muscular contraction. Osmotic
swelling of smooth muscle cells (see Fig. 2) activates a
depolarizing anion conductance, leading to depolarization,
opening of voltage-gated Ca 2/ channels, increase of
intracellular Ca 2/ activity, and contraction (685). Conversely,
osmolar cell shrinkage leads to vasodilation
(1112, 1152).
An enhanced activity of Na / /H / exchanger with resulting
cell swelling has been implicated in the generation
of one type of essential hypertension (271, 314, 348, 558,
664, 793, 887–889, 1022–1024, 1026, 1109, 1124, 1330,
1390). On the one hand, cell swelling should increase contractility
of smooth muscle cells, and on the other hand,
enhanced Na / /H / exchange activity should favor cell proliferation
and thus hypertrophy of vascular smooth mus-
FIG. 3. Polarized cell volume regulatory ion transport in migrating
cells. Cell migrates from left to right. At rear end, oscillations of intracellular
Ca 2/ activity (Cai) lead to activation of Ca 2/ -sensitive K / cle cells. Proliferation of vascular smooth muscle cells
channels,
favoring regulatory cell volume decrease (RVD). At leading edge, Na / has been shown to be stimulated by mechanical stretch
/
H / exchange and Na / -K / -2Cl 0 (770, 979).
cotransport favor regulatory cell volume
increase (RVI). Ca 2/ Neuronal excitability could be affected in several
oscillations further trigger depolymerization of actin
filaments at rear end. Fragments are transported to leading edge,
ways by cell volume. Any release of K where polymerization of actin filaments prevails.
/ for cell volume
regulation should enhance extracellular K / , decrease the
K / equilibrium potential, and thus depolarize the cell chemical K / membrane. Possibly, however, swollen neurons do not
gradient, and thus to impairment of repolar-
ization. Glial cells accumulate K / volume regulate by rapid release of electrolytes (23).
and thus blunt the in-
crease of extracellular K / As discussed in section VE, glutamate, aspartate,
concentration in part by uptake
of K / through Na / -K / -2Cl 0 GABA, glycine, and taurine serve both as osmolytes and
as neurotransmitters. When released from swollen cells,
they may modify the function of neighboring cells (628,
1059). Conversely, the osmosensitive betaine transporter
transports GABA at higher affinity than betaine (1374).
Moreover, sensitivity of neurons to neurotransmitters may
be modified by cell volume. For instance, NMDA receptors
have been found to be mechanosensitive (929). Cell volume
changes may further interfere with neuronal excitability
by modifying the pH and trafficking of secretory
vesicles (see above). Increases of osmolarity have been
shown to increase the percentage of slow miniature endplate
potentials (1262).
Chloride concentration in neurons is regulated by furosemide-sensitive
Na
cotransport in parallel with
/ /
Na -K -ATPase (1298). This function is expected to be
compromised during glial cell swelling. Glial cell swelling
has indeed been implicated in a wide variety of disorders
affecting the brain (505, 624, 649, 650, 896, 898, 1220). In
hepatic encephalopathy, for instance, the enhanced NH3 concentration forces the formation and cellular accumula-
tion of glutamine, leading to glial cell swelling (218, 896,
898). One of the consequences is cellular loss of inositol
(218, 649, 1021). Accordingly, inhibition of glutamine syn-
thetase has been found to be protective against hepatic
encephalopathy (512). A striking increase of brain inositol
is observed in Alzheimer’s disease (1122). It is not clear,
though, whether this change relates to altered cell volume
regulation and contributes to the pathophysiology of this
/ -K / -2Cl 0 cotransport (45, 839). Activation
of K
disease.
/ and Cl 0 channels shrinks the cells by KCl
loss, decreases intracellular Cl
In part as a result of the above interactions, increased
0 concentration, and thus
dissipates the Cl
plasma osmolarity decreases and reduced plasma osmo-
0 gradient. The cell shrinkage activates
the Na
larity increases the susceptibility to epileptic seizures (22,
/ -K / -2Cl 0 cotransport, which not only restores cell 921). It must be kept in mind, though, that alterations of
volume but also maintains intracellular Cl 0 activity. Ac- plasma osmolarity primarily create an osmotic gradient
cordingly, GABA-induced depolarization was rendered across the blood-brain barrier, leading to respective
transient by addition of furosemide (45). Moreover, furo- changes of extracellular space (235, 1125) and movements
semide has been shown to block synchronized burst dis- of electrolytes from or to brain tissue (822). The decrease
charges in hippocampal slices (538). of extracellular space during osmotic cell swelling may
Excitability of neurons critically depends on glial cell
function (612). One of the major tasks of glial cells is to
be a major cause for altered excitability (921, 1224).
maintain constancy of extracellular K / . Because of the
minimal extracellular space, any release of K
G. Migration
/ from neurons
during depolarization would lead to rapid increase Migration involves substantial reorganization of the
of extracellular K / concentration, a dissipation of the cytoskeleton both at the leading edge and the rear of the
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270
LANG ET AL. Volume 78
cell (202, 215, 1162) (see Fig. 3). At the leading edge, both Cl 0 and K / channels via cAMP (337), an effect ex-
polymerization of actin filaments prevails, whereas at the pected to result in cell shrinkage. The heat-stable toxin
rear of the cells, actin filaments are depolymerized (1162). from Escherichia coli has been shown to activate Cl 0
The depolymerization is mediated by capping or escort channels via cGMP (749), and erythrocytes infected with
proteins, such as gelsolin, which are stimulated by Ca 2/ malaria display new ion permeation pathways (633).
(237, 492, 1162, 1355). In fact, after chemotactic stimuli, Moreover, several bacteria produce porins, which may
Ca 2/ concentration increases primarily at the rear of the be inserted into the host cell membrane (97, 771, 1328).
Because porins may function as Cl 0 cell (136, 463, 756). Bound to the capping or escort pro-
channels (1035, 1338),
teins, the actin fragments travel toward the leading edge, it is tempting to speculate that they serve to alter host
where they are reutilized for elongation of the actin fila- cell volume. Exposure of erythrocytes to Schistosoma
ments. The elongation is stimulated by polyphosphoinosi- mansoni membrane fractions has indeed been shown to
tides, which bind and thus neutralize the capping proteins produce marked cell shrinkage (1201). However, whether
(1162). The addition of new elements to the actin filament the metabolic alterations triggered by cell swelling or
is thought to be facilitated by protrusion of the cell mem- shrinkage are favorable for the pathogen is similarly un-
brane, which may be caused by local osmotic swelling known. As outlined above, cell shrinkage inhibits O 0 2 for-
(1162).
mation in neutrophils, an effect possibly contributing to
Migration of leukocytes can be stimulated by chemo- the inhibitory effect on bacterial killing in a hypertonic
attractants such as formylpeptides (727). N-formyl-methi- environment (481). On the other hand, a hypertonic envi-
onyl-leucyl-phenylalanine (FMLP) stimulates Na / /H / co- ronment increases adherence and invasion of Salmonella
transport in neutrophils, leading to cell swelling (842, 870,
typhi (1195).
871, 1003, 1019, 1365). Activation of Na / /H / exchange and Similar scanty information is available on the role of
cell swelling are required for migration, which is impeded cell volume in viral infection. The M2 protein of influenza
by inhibitors of the carrier and osmotic cell shrinkage virus serves as an ion channel (974). Whether the insertion
(1003, 1019). Similarly, inhibition of Na of this channel into the host membrane alters cell volume
/ -K / -2Cl 0 cotransport
with bumetanide inhibited migration of transformed is not known. Tacaribe virus infection was shown to inhibit
Na / -K / MDCK cells (1101). In those cells, migration further re-
-ATPase (996), and vaccinia virus infection
quires the operation of Ca 2/ -sensitive K / channels, which of HeLa cells led to increases of Na / at the expense of
K / are activated by oscillating intracellular Ca (899). Infection of fibroblasts with herpes simplex vi-
2/ activity (240,
1101). Inhibition of these channels similarly prevented rus leads to profound cell swelling (441). Cell swelling
migration. It is attractive to postulate that migration in- was enhanced in the presence of the antiviral drug 3�volves
RVD with Ca 2/ oscillations and activation of K /
azido-3�-deoxythymidine, which inhibits ICln, the putative
volume regulatory Cl 0 channels at the rear and RVI with activation of Na channel (441). Infection of renal
/ /H /
exchange and/or Na / -K / -2Cl 0 cotransport at the leading tubule cells with simian virus 40 results in the appearance
of K / edge of a migrating cell. The migration would require channels (1199). Changes in cell volume, on the
asymmetrical distribution and/or activation of channels other hand, may influence viral replication. For instance,
and carriers. As a matter of fact, the Na a decrease of extracellular NaCl has been shown to reduce
/ /H / exchanger
is concentrated at the leading edge (431) and K / channel replication of reticuloendotheliosis (93) and Sindbis virus
activity at the rear of the cell (1099, 1100), and a Ca (1290) as well as maturation of poliovirus (5). Further-
2/
gradient has been observed within a migrating cell with more, infection of MDCK cells with vesicular stomatitis
virus is impaired by increasing extracellular K / highest values at the rear (136, 401, 463, 1098).
at the
The elongation of the neuritic cylinder, but not the expense of Na / (7), a maneuver known to induce cell
extension of the growth cone of neurons, has been ob- swelling (see Table 2). The effect could not be explained
served to be stimulated by a decrease of extracellular by altered intracellular Ca 2/ activity but was assumed to
osmolarity (117). Accordingly, the role of osmotic gradi- be secondary to a depolarization of the cell membrane (7).
ents in the protrusion of the leading edge is still a matter In duck hepatocytes, increase of extracellular osmolarity
of debate (117, 965, 1162). Obviously, variation of extra- markedly reduced duck hepatitis B virus DNA, mRNA,
cellular osmolarity does more than modify the detach- and protein (904). Because shrinkage of hepatocytes leads
ment of the cell membrane from the cytoskeleton. In any to depolarization (406), the effect could have been due to
case, more experimentation is needed to elucidate the role either depolarization or cell shrinkage.
of cell volume regulatory mechanisms in the machinery of In tracheal epithelium, sulfation and sialation of
migration. membrane proteins has been shown to be sensitive to
H. Pathogen Host Interactions
luminal pH of acidic cellular compartments, and it has
been argued that defective acidification of these compart-
Reports on the interplay of cell volume and infection ments in cystic fibrosis leads to altered sulfation and sialaare
scarce. It is well known that cholera toxin activates tion and thus to enhanced adhesion of Pseudomonas aer-
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January 1998 FUNCTIONAL SIGNIFICANCE OF CELL VOLUME 271
uginosa (54). Because the primary defect of cystic fibrosis
leads to impaired Cl 0 channel activity (92, 170, 171, 350,
1118, 1336, 1337) and impairment of cell volume regulation
(1252), it may be paralleled by cell swelling, which
increases lysosomal pH (see sect. IIIL). Thus cell swelling
could enhance adhesion of P. aeruginosa and infection,
a possibility, however, not yet explored.
Clearly, the role of cell volume in the interaction of
host and pathogen is far from understood. The data available
thus far, however, are sufficiently intriguing to justify
additional experimental effort.
I. Cell Proliferation
A wide variety of mitogenic factors (for review, see
Ref. 1000) activate the Na / /H / exchanger, and many factors
stimulate Na / -K / -2Cl 0 cotransport (85, 428, 826, 844,
928, 1000, 1274, 1275, 1291, 1292, 1293). One expected
consequence of the activation of these transport systems
is an increase of cell volume.
Cell proliferation has indeed been shown to correlate
with increases of cell volume in fibroblasts (694, 695, 824,
960), mesangial cells (1371), lymphocytes (284, 285, 454,
1114, 1117), HL-60 cells (120, 146), GAP A3 hybridoma
cells (884), smooth muscle cells (317, 881), and HeLa cells
(1185). As shown for fibroblasts, the cell volume increase
parallels the entry of fibroblasts from the G1 into the S
phase (960), which is accompanied by inhibition of K
FIG. 4. Cell volume in proliferating cells. Cellular mechanisms trig-
gered by expression of ras oncogene leading to activation or inhibition
of cell volume regulatory mechanisms. Expression of Ras oncogene
(RAS) sensitizes phospholipase C (PLC) for growth promotors such as
bradykinin, bombesin, or serum. As a result, bradykinin-induced forma-
/
channels (253). Moreover, large variations of volume regution
of inositol 1,4,5-trisphosphate (IP3) and inositol 1,3,4,5-tetrakisphos-
phate (IP4) is enhanced. Instead of a single release of cellular Ca 2/ ,
bradykinin induces sustained oscillations of intracellular Ca 2/ latory Cl concen-
0 channels have been observed in ascidian emtration
by triggering both Ca 2/ entry through Ca 2/ channels and Ca 2/
bryos (1273).
release from cellular stores. On one hand, Ca 2/ oscillations cause repeti-
Osmotic alterations of cell volume indeed modify cell tive activation of Ca 2/ -sensitive K / channels, leading to oscillations of
proliferation. Hypertonic shrinkage inhibits (9, 533, 840,
cell membrane potential and transient decrease of cell volume. On the
other hand, Ca 2/ oscillations lead to depolymerization of actin filaments,
967, 1008, 1380) and slight osmotic cell swelling has been / / /
which presumably facilitates activation of Na /H exchanger and Na -
shown to accelerate (18) cell proliferation. When exposed K / -2Cl 0 cotransport. Activation of these carriers results in uptake of
KCl and NaCl. Because Na / is replaced by K / by action of Na / -K / -
to enhanced extracellular ionic strength, the cells may
overcome cell shrinkage by cellular accumulation of os- ATPase, cells accumulate mainly KCl. Ion uptake increases cell volume,
which is one prerequisite for stimulation of cell proliferation. Increase
molytes which then allows them to proliferate normally of cell volume is limited by inhibition of Na / /H / exchanger and Na / -
K / -2Cl 0 (720, 1379, 1380).
cotransport by cell swelling (ICS and ECS stand for intracellular
As illustrated in Figure 4, Ras oncogene expression
in fibroblasts is paralleled by enhanced Na
and extracellular space, respectively).
/ /H / exchange
and Na / -K / -2Cl 0 cotransport activity, leading to an in-
Apparently, the activation of Na / /H / crease of cell volume (694, 695, 824). The increase of
exchange and
Na / -K / -2Cl 0 cotransport is required for stimulation of cell
cell volume is related to oscillations of intracellular Ca 2/
activity (242), which can be triggered by bradykinin, proliferation by ras oncogene (694, 697, 824, 1000). In
bombesin, or serum in those cells (686, 694, 697, 1296, several cell types, cell proliferation is similarly correlated
with enhanced Ca 2/ and K / 1359, 1360). The Ca channel activity (for review,
2/ oscillations cause rapid transient
cell shrinkage due to activation of Ca see Ref. 1000) and is impeded by respective channel inhib-
2/ -sensitive K / chan-
nels (1005, 1358), followed by a sustained increase of cell itors (17, 726, 739, 893, 981, 1091, 1123, 1199, 1256, 1369).
volume presumably due to a depolymerization of the actin However, the activity of certain ion channels and trans-
filaments (243, 1004) and subsequent shift of the set point porters may not always be required for cell proliferation
to occur. Inhibition of the Na / /H / for cell volume regulation (242). The Ca exchanger, for instance,
2/ oscillations are
in turn favored by cell shrinkage (1006), pointing to a is not always found to interfere with cell proliferation (83,
negative-feedback loop (Fig. 4). 189, 598, 827, 1025).
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272
LANG ET AL. Volume 78
How alterations of cell volume interact with cell cycle channel or Kv1.3 via tyrosine phosphorylation (449, 1183),
which is the volume regulatory K / control is not known. As outlined above, cell swelling
channel in lymphocytes
stimulates the protein kinases ERK-1 and ERK-2 (1072), (273). It appears that cell shrinkage interferes at some
proteins probably involved in regulation of cell cycle point with the signaling cascade of apoptotic cell death.
(113).
Fas-induced cell death is triggered by activation of cas-
In proliferating cells, the role of increased cell volume pases with subsequent stimulation of sphingomyelinases,
in altering further volume-sensitive cellular functions ceramide formation, activation of Ras, PI 3-kinase, Rac,
such as alkalinization of lysosomal vesicles (588), de- MKK4, and JNK or p38 kinase (446, 448, 1368). In addition,
creased proteolysis (501), and increased LDL receptor exactivation of Rac triggers formation of active oxygen spe-
pression at the cell surface (1136) has not yet been excies (AOS), presumably by the NADPH oxidase (447). Cell
plored.
shrinkage apparently does not interfere with the cascade
In contrast to cell proliferation, cell differentiation is leading to Ras activation but prevents the formation of
accompanied by cell shrinkage in erythroleukemia cells AOS, since the decrease of GSH is blunted in shrunken
(264, 458, 607, 725), HL-60 leukemic cells (311, 475), and lymphocytes (451).
EMT6/ro mouse mammary sarcoma cells (118). HL-60 Several mechanisms could mediate the inhibition of
cells shrink despite enhanced expression of Na the signaling cascade: cell shrinkage stimulates the expres-
/ /H / exchanger
(986), which displays altered kinetic properties sion of a1-chimerin (see Table 1), a GTPase activating pro-
(227, 228). On the other hand, senescent fibroblasts have tein for Rac. If a similar protein is expressed in lymphocytes
been shown to gain cell volume (960, 961).
as a function of cell volume, it could account for some
inhibition of NADP oxidase activity. Moreover, cell shrink-
J. Cell Death
age inhibits glucose flux through the pentose phosphate
pathway, decreasing the availability of NADPH (see sect.
Apoptotic cell death (617, 1367) is triggered by a wide
variety of factors including stimulation of specific receptors
at the cell membrane, such as the receptor for Fas
(CD95) (1074) or tumor necrosis factor-a (655).
One of the hallmarks of apoptotic cell death is cell
shrinkage (1, 207). Shrinkage may in some cells be sec-
ondary to increased intracellular Ca
VC). Furthermore, hyperosmolarity interferes with the respiratory
burst oxidase (573). Along these lines, hyperos-
motic cell shrinkage blunts agonist-triggered AOS formation
(602, 659, 795, 810), and hyposmotic cell swelling stimulates
AOS formation (602) in polymorphonuclear leukocytes.
Leukocyte AOS production through NADPH oxidase is further
inhibited by high concentrations of urea (1187), which
2/ activity (922, 1226)
and subsequent activation of Ca
at least in some cells leads to cell shrinkage (see sect. IIIA)
2/ -sensitive K / and/or Cl 0
channels. Accordingly, it could be inhibited by K
and similar to osmotic shrinkage inhibits Fas-induced cell
/ channel
blockers or increased extracellular K
death (E. Gulbins and F. Lang, unpublished observations).
/ concentration (55,
61). Stimulation of the Fas-receptor leads to rapid activa-
tion of cell volume regulatory Cl
Although the decreased NADPH availability in
shrunken cells may interfere with endogenous formation of
0 channels (I. Szabo, E.
Gulbins, and F. Lang, unpublished observations) as well
as delayed taurine release, the latter effect paralleling cell
shrinkage (686a). The loss of cell volume may be function-
ally important, since a doubling of extracellular osmolarity
has been shown to trigger apoptosis (109, 811). More-
AOS and thus protects from Fas-induced cell death, it renders
the cells more vulnerable to exogenous oxidative
stress, whereas cell swelling appears to protect from exogenous
oxidative stress (804, 1046).
Beyond the role of AOS, cell shrinkage is expected to
turn on Na / /H / over, the ability of cells to resist osmotic shrinkage by cell
volume regulation paralleled their resistance to apoptosis
after an osmotic shock (109). As discussed in section IIIH,
osmotic stress triggers the MAPK pathway, leading to activation
of JNK via the MAPK kinase (MKK4) (809, 853,
1020, 1216). Both JNK and p38 kinase, another target of
MKK4, have been invoked in the triggering of apoptosis
exchange, leading to alkalinization (see
sect. IIB). Intracellular acidosis, on the other hand, has been
considered a prerequisite for apoptosis (405).
Because cell shrinkage apparently interferes with the
/
Fas signaling pathway, the inhibition of K channels after
activation of the Fas receptor could serve to prevent premature
inhibition of the signaling cascade by cell shrinkage. In
(1368). On the other hand, MKK4 has been postulated to analogy with Fas-induced cell death, methylprednisoloneprotect
from apoptosis (894). Thus the precise function induced apoptosis of thymocytes was observed to be inhib-
ited by low doses of the K / of these kinases in apoptosis remains elusive. Whether
ionophore valinomycin (255).
the proteolytic effect of cell shrinkage (see Table 1) con- Furthermore, tumor necrosis factor-a has been shown to
stimulate Na / /H / tributes to apoptosis remains to be tested.
exchange (1248).
Surprisingly, Fas-induced cell death is inhibited dur- Clearly, the role of cell volume regulatory mechanisms
ing exposure of the cells to moderately hypertonic extrain apoptotic cell death is still ill-defined, and at this point,
cellular fluid (451). Moreover, in lymphocytes, stimulation their functional significance remains a matter of specula-
of the Fas receptor leads to inhibition of the n-type K /
tion.
/ 9j07$$ja07 P18-7 12-30-97 09:41:42 pra APS-Phys Rev

January 1998 FUNCTIONAL SIGNIFICANCE OF CELL VOLUME 273
K. Others
myces cerevisiae, and its expression is regulated by the highosmolarity
glycerol response pathway. Mol. Cell. Biol. 14: 4135–
4144, 1994.
Obviously, a number of further functions involve al-
terations of cell volume and/or activation of volume regulatory
mechanisms.
10. ALBRECHT, J., A. S. BENDER, AND M. D. NORENBERG. Ammonia
stimulates the release of taurine from cultured astrocytes.
Brain Res. 660: 288–292, 1994.
11. ALFIERI, R., P. G. PETRONINI, S. URBANI, AND A. F. BORGH-
Phagocytosis, for instance, could be expected to in-
crease cell volume. Indeed, phagocytotic Kupffer cells do
contain betaine, which is released during phagocytosis
ETTI. Activation of heat shock transcription factor 1 by hypertonic
shock in 3T3 cells. Biochem. J. 319: 601–606, 1996.
12. AL-HABORI, M., M. PEAK, T. H. THOMAS, AND L. AGIUS. The
role of cell swelling in the stimulation of glycogen synthesis by
(1319, 1393). Similarly, the ion channels activated during
phagocytosis (641) may at least in part serve RVD. Moreinsulin.
Biochem. J. 282: 789–796, 1992.
13. ALPER, S. L., H. C. PALFREY, S. A. DERIEMER, AND P. GREEN-
GARD. Hormonal control of protein phosphorylation in turkey
erythrocytes. Phosphorylation by cAMP-dependent and Ca 2/ over, phagocytosis has been shown to be sensitive to am-de-
bient osmolarity (1321).
Activation of thrombocytes is paralleled by excessive
cell shrinkage, which participates in the metamorphosis
pendent protein kinases of distinct sites in goblin, a high molecular
weight protein of the plasma membrane. J. Biol. Chem. 255:
11029–11039, 1980.
14. ALTENBERG, G. A., J. W. DEITMER, D. C. GLASS, AND L. REUSS.
P-glycoprotein-associated Cl 0 of the cells (59).
Furthermore, some evidence points to the involvement
of cell volume regulatory mechanisms during lymphocyte
adhesion, which may play a permissive role in
the activation of Na
currents are activated by cell swell-
ing but do not contribute to cell volume regulation. Cancer Res.
54: 618–622, 1994.
15. ALTENBERG, G. A., C. G. VANOYE, E. S. HAN, J. W. DEITMER,
AND L. REUSS. Relationships between rhodamine 123 transport,
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Binding to L-selectins, with the receptors mediating the 16. ALVAREZ-LEEFMANS, F. J., S. M. GAMINO, AND L. REUSS. Cell
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