Depolarizing agents and tumor necrosis factor-alpha modulate protein phosphorylation in oligodendrocytes

Membrane depolarization and changes in ionic fluxes have been implicated in the signaling mechanisms between neurons and glial cells. We report here that K(+)-induced depolarization of cultured ovine oligodendrocytes (OLGs) decreases the phosphorylation of myelin basic protein (MBP) and 2'3'-cyclic nucleotide phosphohydrolase (CNPase). Membrane depolarization and decrease in phosphorylation of MBP and CNPase can also be elicited by inhibition of the inward rectifier with Ba2+ but not by inhibition of outward K+ channels with 4-aminopyridine or tetraethylammonium. These findings demonstrate that modulation of K+ currents can influence phosphorylation states of OLG proteins. Tumor necrosis factor-alpha (TNF-alpha), an immune peptide implicated in autoimmune demyelinating diseases, also inhibits the phosphorylation of these proteins. In contrast to elevated [K+]o, TNF-alpha does not decrease the stimulatory effect of protein kinase C activators or phosphatase inhibitors on MBP and CNPase phosphorylation, suggesting that depolarizing agents and TNF-alpha act via distinct mechanisms. We postulate that the presence of elevated extracellular K+ and/or cytokines under certain pathological conditions can perturb OLG function by altering the phosphorylation states of their proteins and perhaps affect myelin maintenance, contributing to demyelination.