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.
Soliven
B
B
Department of Neurology, University of Chicago, Illinois 60637.
Takeda
M
M
Szuchet
S
S
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D002478:Cells, Cultured; D008564:Membrane Potentials / Q000187:drug effects; D004676:Myelin Basic Protein / Q000096:biosynthesis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology*; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012756:Sheep; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D009467:Neuromuscular Depolarizing Agents; D015221:Potassium Channels; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C; D010744:Phosphoric Monoester Hydrolases; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D010727:Phosphoric Diester Hydrolases; D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; D011188:Potassium