Functional Significance of Cell Volume Regulatory Mechanisms
Functional Significance of Cell Volume Regulatory Mechanisms
Functional Significance of Cell Volume Regulatory Mechanisms
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250<br />
LANG ET AL. <strong>Volume</strong> 78<br />
RVI is paralleled by inhibition <strong>of</strong> ion release mechanisms. In many cells, swelling leads to the activation <strong>of</strong> non-<br />
Thus the simultaneous stimulation <strong>of</strong> ionic mechanisms selective cation channels (for review, see Refs. 682, 1040,<br />
for RVD and RVI is largely avoided (927, 938). A tremen- 1043). Because with the negative potential difference<br />
dous amount <strong>of</strong> work has been dedicated to the elucida- across the cell membrane the net driving force for cation<br />
tion <strong>of</strong> the ion transport systems in different tissues. A movement is directed into the cell, ion movement through<br />
synopsis <strong>of</strong> tissue-specific transport systems is beyond these channels cannot be expected to directly serve cell<br />
the scope <strong>of</strong> this review and has been reviewed in detail volume regulation. However, these channels allow the<br />
passage <strong>of</strong> Ca 2/ elsewhere (682).<br />
, which then enters the cells and activates<br />
1. <strong>Regulatory</strong> cell volume decrease<br />
Ca 2/ -sensitive K / channels (187, 1194, 1234).<br />
Usually more cations (K / and Na / ) are lost from cells<br />
than Cl 0 (436, 476, 998). The difference is partially due to<br />
loss <strong>of</strong> HCO 0 3 . Most HCO 0 The transport systems most <strong>of</strong>ten activated by cell<br />
3 lost is replaced by CO2, and<br />
swelling are separate K / and anion channels. In several the H / thus generated is bound to intracellular buffers.<br />
Thus the exit <strong>of</strong> HCO 0 studies, the anion channels activated by cell swelling have<br />
3 is limited by the intracellular buffer<br />
been found to be nonselective, allowing the passage not capacity (346, 738). The HCO 0 3 that is replaced by CO2<br />
only <strong>of</strong> Cl does not directly contribute to cell volume regulation but<br />
0 but also <strong>of</strong> HCO 0 3 (690, 1334) and even organic<br />
anions and neutral organic osmolytes (176, 576, 632, 1034, allows the cellular loss <strong>of</strong> K / .<br />
1169).<br />
Osmotic cell swelling decreases the gap junctional<br />
Obviously, different channel proteins from different conductance (890, 1002), an effect in part due to decrease<br />
families are utilized for cell volume regulation. Among the <strong>of</strong> intracellular ion concentration.<br />
cloned K / channels invoked to serve cell volume regula- Decreasing extracellular osmolarity activates Na /<br />
tion are the Kv1.3 (N-type K channels in the frog skin (126, 226), urinary bladder (329,<br />
/ channel) (273), the Kv1.5<br />
channel (316), and the minK channel (150, 151). Cloned 740), and A6 cells (234), an effect, however, not related<br />
Cl to cell volume regulation.<br />
0 channels invoked in cell volume regulation include<br />
the ClC-2 channel (435, 584, 585, 760, 1203), BRI-VDAC<br />
(272), ICln (158, 439, 440, 910, 948, 949), and the P-glycoprotein<br />
(or MDR protein) (362, 464, 1015, 1225, 1249, 1250).<br />
2. <strong>Regulatory</strong> cell volume increase<br />
Alternatively, P-glycoprotein (490, 532, 589, 590) and ICln The major ion transport systems accomplishing electrolyte<br />
accumulation in shrunken cells are the Na / -K / (647) were suggested to regulate the volume regulatory<br />
-<br />
Cl 0 channel. However, the role <strong>of</strong> P-glycoprotein in cell 2Cl 0 cotransporter (294, 381) and the Na / /H / exchanger<br />
volume regulation has been questioned (14, 15, 160, 256,<br />
(420). The latter alkalinizes the cell leading to parallel<br />
257, 663, 764, 988, 1217, 1269). Clearly, many <strong>of</strong> the proper- activation <strong>of</strong> the Cl 0 /HCO 0 3 exchanger. The H / and<br />
HCO 0 3 exchanged for NaCl by the Na / /H / ties <strong>of</strong> cell volume regulatory anion channels are not ex-<br />
exchanger and<br />
plained by the known cloned channels (539), and addi- the Cl 0 /HCO 0 3 exchanger are replenished within the cell<br />
tional anion channels must be operative. In addition,<br />
from CO 2, which diffuses into the cell and is thus osmoti-<br />
Na / (HCO 0 3 ) n cotransport may participate in RVD (1281). cally not relevant.<br />
Among the cloned members <strong>of</strong> the Na / /H / Apart from ion channels, the most frequently utilized<br />
exchanger<br />
transport system for KCl exit is electroneutral KCl co- family (1294), NHE-1 (266), NHE-2 (266, 601), and NHEtransport<br />
(708–710, 963, 1206; for review, see Ref. 682). 4 (107) are stimulated, whereas NHE-3 (86, 87, 266, 601)<br />
This transporter appears to be activated preferably by is inhibited by cell shrinkage. The putative volume-sensi-<br />
isotonic cell swelling (374). Some cells apparently release tive site at the NHE-1 molecule has been identified and is<br />
KCl by parallel activation <strong>of</strong> K / /H / exchange and Cl 0 / distinct from the sites regulated by Ca 2/ and growth fac-<br />
HCO tors (86). The cloned anion exchanger AE2 but not AE1<br />
0 3 exchange (103, 161). The H / and HCO 0 3 exchanged<br />
for KCl form CO2, which then diffuses out <strong>of</strong> the cell is postulated to participate in RVI (587).<br />
Several members <strong>of</strong> the volume regulatory Na / -K / and is thus not osmotically active. Beyond that, the anion<br />
-<br />
exchanger (AE1) has been implicated in activation <strong>of</strong> vol- 2Cl 0 cotransporters have been cloned (265, 364, 951, 952,<br />
1370). In muscle cells, NaCl cotransport rather than Na / ume regulatory ion channels (374, 861).<br />
-<br />
Swelling <strong>of</strong> Na / -rich erythrocytes is thought to stimu- K / -2Cl 0 cotransport is utilized for NaCl uptake (288).<br />
late Na However, little is known about the volume regulatory role<br />
/ extrusion through reversal <strong>of</strong> Na / /Ca 2/ exchange,<br />
and parallel extrusion <strong>of</strong> Ca 2/ by the Ca 2/ -ATPase (932). <strong>of</strong> the cloned NaCl cotransporters (365).<br />
Alternatively, evidence has been presented for the activa- In some cells, electrolyte accumulation during RVI is<br />
tion <strong>of</strong> ouabain-insensitive Na / -ATPase or Na / -K / -ATPase accomplished by activation <strong>of</strong> Na / channels and/or nonse-<br />
(850). Swelling has been shown to stimulate (1263) or<br />
lective cation channels (159, 177, 1278, 1332). The depolar-<br />
inhibit (1342) the Na / -K / -ATPase. The gastric K / -H / - ization induced by the Na / entry favors Cl 0 entry into the<br />
ATPase is stimulated by cell swelling (1113).<br />
cell.<br />
/ 9j07$$ja07 P18-7 12-30-97 09:41:42 pra APS-Phys Rev