Functional Significance of Cell Volume Regulatory Mechanisms

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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-
/ 9j07$$ja07 P18-7 12-30-97 09:41:42 pra APS-Phys Rev