Myelin basic protein (MBP) is the major extrinsic membrane protein of central nervous system myelin. MBP phosphorylation at Threonine 125 is a complex regulatory process that modulates the contribution of MBP to the stability of the myelin sheath. Mitogen-activated protein kinases modulate MBP phosphorylation during myelinogenesis and in the demyelinating disease multiple sclerosis. MBP phosphorylation is regulated by high-frequency stimulation but not low-frequency stimulation of the alveus, the myelinated output fibers of the hippocampus. It is proposed that during periods of increased neuronal activity, calcium activates axonal nitric oxide synthase, which generates the intercellular messengers nitric oxide and superoxide and regulates the phosphorylation state of MBP by MAPK.