Functional Significance of Cell Volume Regulatory Mechanisms

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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 hemoglobin (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/ concentration. 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 accomplished by entry mechanisms across one cell membrane and ion exit mechanisms at the other cell membrane. Obviously, the entry or extrusion of osmotically active substances 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 kidney, 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, / 9j07$$ja07 P18-7 12-30-97 09:41:42 pra APS-Phys Rev
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). / 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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