Functional Significance of Cell Volume Regulatory Mechanisms

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252 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 glutamine (238, 239). Amino acids are probably important during 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 accumulation (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 modify the concentrations of these metabolites and thus contribute 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- / 9j07$$ja07 P18-7 12-30-97 09:41:42 pra APS-Phys Rev
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 / 9j07$$ja07 P18-7 12-30-97 09:41:42 pra APS-Phys Rev
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