MEMBRANE DEPOLARIZATION AND CALCIUM INFLUX STIMULATE MEK AND MAP KINASE VIA ACTIVATION OF RAS

A pathway by which calcium influx through voltage-sensitive calcium ch annels leads to mitogen-activated protein kinase (MAPK) activation has been characterized. In PC12 cells, membrane depolarization leading to calcium influx through L-type calcium channels activates the dual spe cificity MAPK kinase MEK1, which phosphorylates and activates MAPK. Ca lcium influx leads within 30 s to activation of the small guanine nucl eotide-binding protein pas. Moreover, activation of MAPK in response t o calcium influx is inhibited by the dominant negative mutant Ras(ASN1 7), indicating that pas activity is required for calcium signaling to MAPK. Ras is also activated by release of calcium from intracellular s tores and by membrane depolarization of primary cortical neurons. The pleiotropic regulatory potential of both Ras and the MAPK pathway sugg ests that they may be central mediators of calcium signaling in the ne rvous system.