Carnitine prevents NMDA receptor-mediated activation of MAP-kinase and phosphorylation of microtubule-associated protein 2 in cerebellar neurons in culture

Activation of N-methyl-D-aspartate (NMDA) receptors leads to increased phosphorylation of the microtubule-associated protein MAP-2 by a mechanism that involves activation of nitric oxide synthase and nitric oxide-induced activation of mitogen-activated protein kinase (MAP-kinase). We have assessed the effects of carnitine on this signal transduction pathway in primary cultures of rat cerebellar neurons. We show that carnitine inhibits NMDA-induced phosphorylation of MAP-2 and that this is due to decreased activation of MAP-kinase. This effect is not due to inhibition by carnitine of NMDA-induced activation of nitric oxide synthase or to quenching of the nitric oxide formed, which are not affected by carnitine. Carnitine also inhibits the increase in phosphorylation of MAP-2 induced by the nitric oxide-generating agent S-nitroso-N-acetylpenicillamine, but not nitric oxide-induced activation of soluble guanylate cyclase. These results indicate that carnitine interferes with NMDA-induced, nitric oxide mediated activation of MAP-kinase at a step subsequent to nitric oxide formation.