Functional Significance of Cell Volume Regulatory Mechanisms

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LANG ET AL. Volume 78
well as swelling-induced osmolyte efflux (1037), increases Cl 0 channels and K / channels. To the extent that in those
of intracellular Ca cells cAMP is increased after cell swelling, cAMP partici-
2/ concentration (30), mitogen-activated
protein kinase (MAPK) activity (895, 1072), vesicu- pates in cell volume regulation. Beyond that, cAMP has
lar acidification (1088), and swelling-induced stimulation been postulated to shift the volume regulatory set point
of taurocholate excretion (895), suggesting that G proteins of the channel toward smaller volumes (823).
do mediate some effects of cell swelling. Activation of Additional experimental evidence points to the
the Na / /H / exchanger during cell shrinkage has similarly involvement of various kinases in volume regulation of
been claimed to involve G proteins (108, 249).
different cell types. In intestinal cells, volume regulatory
In addition to heterotrimeric G proteins, small G pro- rubidium efflux was inhibited by herbimycin A and gen-
teins have been implicated in cell volume regulation. Closistein, pointing to involvement of tyrosine kinase (1211).
tridium botulinus C3 exoenzyme, which depolymerizes Swelling of Jurkat cells activates the src-like tyrosine kinase
p56 lck the actin filament network by ADP-ribosylation of rho
, which in turn accounts for the activation of
(8), blunts the volume regulatory anion efflux (1209). In the volume regulatory Cl 0 channels (727a). Wortmannin,
neurons, osmotic cell shrinkage stimulates the expression an inhibitor of PI 3-kinase, similarly interferes with cell
of a1-chimerin (286), a GTPase-activating protein that in- volume regulation in those cells (1209). In proximal tubules
activates the small G protein Rac. The impact of this effect (1012–1014) and in HeLa cells (490), protein kinase C has
on cell volume regulation is not explored. been invoked to link cell swelling to activation of Cl 0 channels.
Cell swelling leads to phosphorylation of the anion
H. Protein Phosphorylation
exchanger, which was postulated to release taurine (869).
In addition to its role in the phosphorylation of pro-
1. Cell swelling
teins, ATP may serve as a signaling molecule itself. The
volume regulatory Cl 0 channel in collecting duct, glioma,
Mechanical stress or cell swelling has been found to and intestine 470 cells (908, 1277) as well as taurine efflux
stimulate protein kinase C (997, 1017) to foster tyrosine in skate hepatocytes and glioma cells (47, 575, 1277) are
phosphorylation of several proteins including focal adhe- apparently regulated by intracellular ATP concentration.
sion kinase p125 FAK (1209, 1211), to stimulate phosphati- Decreased ATP concentration, as it occurs during energy
dylinositol 3-kinase (PI 3-kinase) (1209), and to trigger depletion, inhibited the channel. In pancreatic b-cells, cell
MAPK cascades leading to the activation of Jun-NH2-ter- swelling leads to activation of ATP-sensitive K / channels
minal kinase (JNK) or extracellular signal-regulated ki- (289a). Extracellular ATP has been shown to stimulate
nases ERK-1 and ERK-2 (4, 360, 482, 568, 569, 895, 1044, taurine release from tracheal cells (362). It has been spec-
1072, 1073, 1127, 1211). Adenylate cyclase has been reulated that after cell swelling ATP is extruded via the
ported to be stimulated (851, 1324–1326) and inhibited cystic fibrosis transmembrane conductance regulator and
activates K / channels and Cl 0 (535) by cell swelling, and cAMP has been shown to inhibit
channels from the extracelvolume
regulatory Cl 0 channels in chicken hearts (468). lular side (1030, 1310). On the other hand, extracellular
ATP has been shown to inhibit volume regulatory Cl 0
Most recently, we have successfully cloned a cell volumeregulated
serine/threonine kinase, the human serum glucocorticoid-dependent
kinase h-sgk (1295). Expression of
channels in intestinal cells (1228).
this kinase is rapidly upregulated by moderate cell shrinkage
and markedly depressed by moderate cell swelling.
2. Cell shrinkage
How these events link to activation of the various Similar to cell swelling, osmotic cell shrinkage has
volume regulatory mechanisms is poorly understood. The been shown to activate protein kinase C (702), whereas
volume regulatory KCl cotransport is activated by dephos- cAMP formation (648) and cAMP-dependent phosphoryla-
phorylation and inactivated by phosphorylation (94, 295, tion have been shown to remain unaffected (13, 648). In
580, 581, 597, 920, 1144). Swelling or increased hydrostatic several cell types, osmotic shrinkage stimulates the phos-
pressure was suggested to inhibit a kinase, favoring dephorylation of myosin light chains, an effect presumably
phosphorylation (94, 295, 386, 580), but nothing is known related to activation of Na / -K / -2Cl 0 cotransport (635, 903,
about the properties of this kinase, which appears to be 1188).
distinct from protein kinases A and C (581). Some evi- Excessive osmotic cell shrinkage, such as doubling
dence indicates the involvement of the cytoskeleton in of extracellular osmolarity, triggers several proteins in-
the swelling-induced inhibition of the kinase (539). On the volved in the MAPK pathways, such as Raf-1, MAPK ki-
other hand, the view that phosphorylation or dephosphornase, MAPK, and ribosomal protein S6 kinase (809, 1197)
ylation links cell swelling to activation of KCl cotransport or activation of JNK by the MAPK kinase MKK4 (853),
has been challenged (1041).
which may be triggered by the tyrosine kinase Pyk2
The volume of a wide variety of cells is decreased by through a pathway requiring activation of PI 3-kinase and
cAMP (see Table 2), an effect mainly due to activation of the small G proteins Ras and Rac (1216). The activation
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