cAMP cascade leads to Ras activation in cortical neurons

Monoaminergic G protein-coupled receptors (GPCRs) are highly expressed in t he CNS at the cerebrocortical level, where they support a variety of behavi oural responses. To elucidate possible intracellular signalling pathways co upled to these receptors, we have studied their ability to activate extrace llular signal-regulated kinases (ERKs) in cultured cortical neurons. An inc rease in ERK activity was observed after stimulation of neurons with dopami ne or serotonin, and with agonists selective for various GPCRs. In addition , ERK activation was also observed following treatment with phorbol dibutyr ate (PdBu) and forskolin, activators of protein kinase C (PKC) and protein kinase A (PKA), respectively. Concomitant with ERK activation, all the mono aminergic agonists tested also increased the level of active Ras (Ras-GTP). Surprisingly, Ras activation was also observed after activation of cAMP pa thway, and this effect was at least in part mediated by PKA. Ras activation by cAMP was unique for neurons, since in PC12 cells forskolin caused activ ation of ERK but did not increase Ras-GTP level. These results highlight th e relevance of Ras as a target for multiple signalling cascades leading to activation of the ERK pathway in neurons. (C) 2000 Elsevier Science B.V. Al l rights reserved.