Functional Significance of Cell Volume Regulatory Mechanisms

266
LANG ET AL. Volume 78
TABLE 3. Influence of cell volume on metabolism the cell swelling effect of the hormone. Conversely, glucagon
and cAMP stimulate proteolysis and glycogenolysis
Effect Process Affected
and inhibit protein synthesis in part by cell shrinkage due
/ Glycogen synthesis in hepatocytes (4, 12, 50, 51, 53, 455,
456, 555, 819, 953) and muscle (762)
to activation of ion channels and subsequent release of
KCl (504). Although cell shrinkage correlates well with
0
0
/
Glycogenolysis (406, 696)
Glucose-6-phosphatase activity (409)
Glucokinase activity in hepatocytes (1261)
the inhibitory effect of cAMP and ADH on protein synthesis,
this is not true for the effects of insulin and phenyleph-
0 Glycolysis in muscle and fibroblasts (196, 918) rine (1159). Thus cell volume may play a less prominent
/
/
/
Glycolysis in hepatocytes (953)
Macrophages and lymphocytes (1366)
Lactate uptake in hepatocytes (696)
Pentose phosphate shunt in hepatocytes (496, 1046)
role in hormonal regulation of protein synthesis than in
proteolysis. The same probably holds true for glycogen
metabolism and lipogenesis.
0
/
Release of glutamine and alanine from muscle (945)
Protein synthesis in hepatocytes (1007, 1159), HeLa cells
(1008, 1343), and mammary cells (825)
The antiproteolytic effect of cell swelling depends on
an intact microtubule network (156, 1284) and could thus
0
/
/
Proteolysis in hepatocytes (471, 472, 498, 499, 767, 1284,
1285, 1287)
Amino acid uptake (100, 500, 502)
Glutamine breakdown in liver (502), lymphocytes, and
macrophages (1366)
not be reproduced in freshly isolated hepatocytes (820),
which suffer from a disintegrated microtubule network
(511, 1284).
The set points of volume regulatory mechanisms and
0
/
/
Glutamine synthesis (502)
Glycine and alanine oxidation (496, 510, 676)
Urea synthesis from amino acids (505)
thus cell volume can be altered by a wide variety of other
hormones and transmitters, which thus trigger the meta-
0 Urea synthesis from NH / 4 (500, 502) bolic pattern typical for swollen or shrunken cells (Table
/
0
/
Glutathione (GSH) efflux (503)
GSSG release into bile (1046)
Ornithine decarboxylase activity and expression (769,
1). By this means, the mediators exploit volume regulatory
mechanisms to exert their effects on cellular metabolism.
1215) In addition to hormones, nutrients may modify pro-
/
/
/
RNA and DNA synthesis in HeLa cells (1008)
Ketoisocaproate oxidation (510)
Acetyl CoA carboxylase (49, 51, 53, 555)
tein, glycogen, and lipid metabolism in part through their
influence on cell volume. In fact, the antiproteolytic effect
/ Lipogenesis (51) of glutamine and glycine in liver has been shown to be
0
/
/
Carnitine palmitoyltransferase I activity (457, 841, 1389)
Taurocholate excretion into bile (469, 497, 508)
Respiration in glial cells (609) and sperm (231)
completely accounted for by their influence on cell volume
(471). The antiproteolytic and swelling effect of gly-
0
0
/
Cellular ATP concentration in hepatocytes (820)
Phosphocreatine concentrations in glioma cells (747)
Formation of active oxygen species in neutrophils (658,
659)
cine is potentiated after starvation (471, 1285), which
upregulates the glycine transporting system A (515). However,
the antiproteolytic action of other amino acids such
/ Bile secretion (497) as phenylalanine, serine, alanine, and proline cannot be
/, Stimulation upon cell swelling and/or inhibition by cell shrinkage;
0, inhibition upon cell swelling and/or stimulation by cell shrinkage.
For effects on gene expression, see Table 1. For effects on intracellular
fully explained by their effects on cell volume. Thus mechanisms
other than cell swelling contribute to the antiproteolytic
action of some amino acids.
signaling, see text. Reference numbers are given in parentheses. The influence of cell volume on metabolism is not
restricted to macromolecular synthesis and breakdown.
C. Regulation of Metabolism
Swelling of hepatocytes apparently interferes with the
transfer of reducing equivalents through the mitochondrial
malate/aspartate shuttle (503). The lack of aspartate
As listed in Table 3, cell volume changes modify a impedes the formation of urea from NH3, an effect that
wide variety of metabolic functions. Most importantly, is overcome by addition of lactate and pyruvate, allowing
cell swelling favors the synthesis and inhibits the degrada- the mitochondrial regeneration of oxaloacetate (503). The
tion of proteins, glycogen, and to a lesser extent lipids formation of urea from glutamine is enhanced after cell
(504, 506). Cell shrinkage has the opposite effect. Thus swelling (500).
cell swelling can be considered as an anabolic signal, Some effects of cell swelling caused by a decrease
whereas cell shrinkage favors cell catabolism.
of extracellular osmolarity may actually be due to con-
In hepatocytes, the influence of cell volume on metab- comitant mitochondrial swelling (969) because of de-
olism is one way that insulin and glucagon exert their creasing ambient osmolarity. Glutamine breakdown (502)
metabolic effects. Insulin increases liver cell volume by and glycine oxidation (510), for instance, are stimulated
activation of Na not only by decrease of extracellular osmolarity but also
/ /H / exchange and Na / -K / -2Cl 0 cotransport
and thus triggers a variety of metabolic functions, by glucagon, cAMP, and several Ca 2/ -mobilizing hor-
including protein and glycogen synthesis and inhibition mones that swell mitochondria (465–467), but at the same
of protein and glycogen degradation (4, 504, 506). The time shrink hepatocytes (see Table 2). Similarly, the
effect of insulin on proteolysis is fully accounted for by swelling-induced decrease of the b-hydroxybutyrate-to-
/ 9j07$$ja07 P18-7 12-30-97 09:41:42 pra APS-Phys Rev