Glutamate-stimulated calcium activation of Ras/Erk pathway mediated by nitric oxide

NMDA-type glutamate receptor-mediated increases in intracellular calcium pl ay a critical role in synaptic plasticity involved in learning and memory. Calcium-dependent activation of Ras and extracellular signal-regulated kine ses (Erks) may transmit the glutamate signal to the nucleus which is ultima tely important for long-lasting neuronal responses. The mechanism by which changes in cytoplasmic calcium mediate NMDA-induced activation of Ras and E rk is not known. In cerebral cortical neurons, this calcium influx through NMDA receptors activates Ras and its downstream effector, Erk, via nitric o xide (NO) generation by calcium-dependent neuronal NO synthase. We propose that NO is a key link between NMDA-mediated increases in cytoplasmic calciu m and activity-dependent long-term changes such as differentiation, surviva l and synaptic plasticity. (C) 1999 Elsevier Science Ireland Ltd. All right s reserved.