p38 MAP kinase modulates liver cell volume through inhibition of membrane Na+ permeability

In hepatocytes, Na+ influx through nonselective cation (NSC) channels repre sents a key point for regulation of cell volume. Under basal conditions, ch annels are closed, but both physiologic and pathologic stimuli lead to a la rge increase in Na+ and water influx. Since osmotic stimuli also activate m itogen-activated protein (MAP) kinase pathways, we have examined regulation of Na+ permeability and cell volume by MAP kinases in an HTC liver cell mo del. Under isotonic conditions, there was constitutive activity of p38 MAP kinase that was selectively inhibited by SB203580. Decreases in cell volume caused by hypertonic exposure had no effect on p38, but increases in cell volume caused by hypotonic exposure increased p38 activity tenfold. Na+ cur rents were small when cells were in isotonic media but could be increased b y inhibiting constitutive p38 MAP kinase, thereby increasing cell volume. T o evaluate the potential inhibitory role of p38 more directly, cells were d ialyzed with recombinant p38 alpha and its upstream activator, MEK-6, which substantially inhibited volume-sensitive currents. These findings indicate that constitutive p38 activity contributes to the low Na+ permeability nec essary for maintenance of cell volume, and that recombinant p38 negatively modulates the set point for volume-sensitive channel opening. Thus, functio nal interactions between p38 MAP kinase and ion channels may represent an i mportant target for modifying volume-sensitive liver functions.