Evidence suggests that membrane depolarization is able to promote neuronal survival through a sustained, although moderate, increase in the intracellular calcium. We have used the PC12 cell line to study the possible intracellular pathways that can be activated by calcium influx. Previously, we observed that membrane depolarization-induced calcium influx was able to activate the extracellular-regulated kinase (ERK)/mitogenactivated protein kinase pathway and most of this activation was calmodulin-dependent. We demonstrated that a part of the ERK activation is due to the phosphorylation of the epidermal growth factor receptor. Here, we show that both the epidermal growth factor receptor phosphorylation and the Shc-Grb2-Ras activation are not calmodulin-modulated. Moreover, dominant negative mutant Ha-ras (Asn-17) prevents the activation on ERKs by membrane depolarization, suggesting that Ras and calmodulin are both necessaries to activate ERKs by membrane depolarization. We failed to observe any significant induction and/or modulation of the A-Raf, B-Raf or c-Raf-1 kinase activities, thus suggesting the existence of a MEK kinase different from the classical Raf kinases that directly or indirectly can be modulated by Ca21/calmodulin.