CALMODULIN IS INVOLVED IN MEMBRANE DEPOLARIZATION-MEDIATED SURVIVAL OF MOTONEURONS BY PHOSPHATIDYLINOSITOL-3 KINASE-INDEPENDENT AND MAPK-INDEPENDENT PATHWAYS

In the present work, we find that the elevation oi extracellular K+ co ncentration promotes the survival of chick spinal cord motoneurons in vitro deprived of any neurotrophic support, This treatment induces chr onic depolarization of the neuronal plasma membrane, which activates L -type voltage-dependent Ca2+ channels, resulting in Ca2+ influx and el evation of the cytosolic free Ca2+ concentration, Pharmacological redu ction of intracellular free Ca2+ or withdrawal,al of extracellular Ca2 + reversed the effects of depolarization on survival. The intracellula r Ca2+ response to membrane depolarization developed as an initial pea k followed by a sustained increase in intracellular Ca2+ concentration . The depolarizing treatment caused tyrosine phosphorylation of mitoge n-activated protein kinase (MAPK) without involving tyrosine kinase re ceptor activation, The calmodulin antagonist W13 inhibited the surviva l promoting effect induced by membrane depolarization but not the tyro sine phosphorylation of MAPK. Moreover, depolarization did not induce phosphatidylinositol-3 kinase (PI-3K) phosphorylation in our cells, an d the PI-3K inhibitor wortmannin did not suppress the survival-promoti ng effect of K+ treatment. These results suggest that calmodulin is in volved in calcium-mediated survival of motoneurons through the activat ion of PI-3K- and MAPK-independent pathways.