Abstract

In the present work, we find that the elevation of extracellular K⁺ concentration promotes the survival of chick spinal cord motoneurons in vitro deprived of any neurotrophic support. This treatment induces chronic depolarization of the neuronal plasma membrane, which activates L-type voltage-dependent Ca²⁺ channels, resulting in Ca²⁺influx and elevation of the cytosolic free Ca²⁺concentration. Pharmacological reduction of intracellular free Ca²⁺ or withdrawal of extracellular Ca²⁺ reversed the effects of depolarization on survival. The intracellular Ca²⁺ response to membrane depolarization developed as an initial peak followed by a sustained increase in intracellular Ca²⁺concentration. The depolarizing treatment caused tyrosine phosphorylation of mitogen-activated protein kinase (MAPK) without involving tyrosine kinase receptor activation. The calmodulin antagonist W13 inhibited the survival-promoting effect induced by membrane depolarization but not the tyrosine phosphorylation of MAPK. Moreover, depolarization did not induce phosphatidylinositol-3 kinase (PI-3K) phosphorylation in our cells, and the PI-3K inhibitor wortmannin did not suppress the survival-promoting effect of K⁺ treatment. These results suggest that calmodulin is involved in calcium-mediated survival of motoneurons through the activation of PI-3K- and MAPK-independent pathways.