Na+,K(+)-ATPase in the choroid plexus. Regulation by serotonin/protein kinase C pathway

In the choroid plexus, the ion pump Na+,K(+)-ATPase regulates the production of cerebrospinal fluid. We now report that incubation of choroid plexus with an activator of protein kinase C, phorbol 12,13-dibutyrate, strongly stimulates the phosphorylation of Na+,K(+)-ATPase and inhibits its activity. Similar effects were obtained with serotonin, which in the choroid plexus stimulates phosphoinositide turnover, thereby activating protein kinase C. Serotonin (10 microM) increased by about 10-fold the amount of phosphorylated Na+,K(+)-ATPase and significantly reduced its activity. Two-dimensional peptide mapping showed comigration of Na+,K(+)-ATPase phosphorylated by either phorbol 12,13-dibutyrate or serotonin in intact cells and by protein kinase C in vitro. These results demonstrate that first messengers can regulate the activity of Na+,K(+)-ATPase through a mechanism involving protein phosphorylation. Moreover, they provide a plausible mechanism for the demonstrated ability of serotonin to decrease cerebrospinal fluid production.