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 sheath. Recent research has demonstrated the modulation of MBP phosphorylation by mitogen-activated protein kinase (MAPK) during myelinogenesis and in the demyelinating disease multiple sclerosis. Here we investigated the physiological regulation of MBP phosphorylation by MAPK during neuronal activity in the alveus, the myelinated output fibers of the hippocampus. Using a phosphospecific antibody that recognizes the predominant MAPK phosphorylation site in MBP, Thr95, 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 change in MBP phosphorylation was attenuated by the reactive oxygen species scavengers superoxide dismutase and catalase and the nitric oxide synthase inhibitor N-nitro-L-arginine. Removal of extracellular calcium also blocked the changes in MBP phosphorylation. Thus, we propose 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.
Atkins
C M
CM
Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Yon
M
M
Groome
N P
NP
Sweatt
J D
JD
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015153:Blotting, Western; D002118:Calcium / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology* / Q000502:physiology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D004676:Myelin Basic Protein / Q000276:immunology / Q000378:metabolism*; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013912:Threonine / Q000378:metabolism
D000906:Antibodies; D007527:Isoenzymes; D004676:Myelin Basic Protein; D017382:Reactive Oxygen Species; D013912:Threonine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium