Functional Significance of Cell Volume Regulatory Mechanisms

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250 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. / 9j07$$ja07 P18-7 12-30-97 09:41:42 pra APS-Phys Rev
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 electrolyte 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 compatible 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 phosphodiesterase 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). / 9j07$$ja07 P18-7 12-30-97 09:41:42 pra APS-Phys Rev
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Functional Significance of Cell Volume Regulatory Mechanisms

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