Regulation of myelin basic protein phosphorylation by mitogen-activated protein kinase during increased action potential firing in the hippocampus

Myelin basic protein (MBP) phosphorylation is a complex regulatory process that modulates the contribution of MBP to the stability of the myelin sheat h. Recent research has demonstrated the modulation of MBP phosphorylation b y mitogen-activated protein kinase (MAPK) during myelinogenesis and in the demyelinating disease multiple sclerosis, Here we investigated the physiolo gical regulation of MBP phosphorylation by MAPK during neuronal activity in the alveus, the myelinated output fibers of the hippocampus. Using a phosp hospecific antibody that recognizes the predominant MARK phosphorylation si te in MBP, Thr(95), We found that MBP phosphorylation is regulated by high- frequency stimulation but not low-frequency stimulation of the alveus. This change was blocked by application of tetrodotoxin, indicating that action potential propagation in axons is required. It is interesting that the chan ge in MBP phosphorylation was attenuated by the reactive oxygen species sca vengers superoxide dismutase and catalase and the nitric oxide synthase inh ibitor N-nitro-L-arginine. Removal of extracellular calcium also blocked th e changes in MBP phosphorylation. Thus, we propose that during periods of i ncreased neuronal activity, calcium activates axonal nitric oxide synthase, which generates the intercellular messengers nitric oxide and superoxide a nd regulates the phosphorylation state of MBP by MAPK.