G(i)-mediated activation of the p21(ras)-mitogen-activated protein kinase pathway by α₂-adrenergic receptors expressed in fibroblasts

The α₂-adrenergic receptors are linked to inhibition of adenylylcyclase and, under certain circumstances, to stimulation of phospholipid hydrolysis via pertussis toxin-sensitive G proteins. Here we show that α₂-adrenergic receptors can couple to an alternative signaling pathway. When expressed in Rat-1 cells, stimulation of the α(2A) receptor, which couples to G(i2) and G(i3), causes rapid, transient activation of the protooncogene product p21(ras) as measured by an increase in the amount of bound GTP. Furthermore, α(2A) receptor stimulation causes rapid phosphorylation of the p42 mitogen- activated protein (MAP) kinase. Pertussis toxin completely inhibits both p21(ras) activation and MAP kinase phosphorylation, but both responses appear to be independent of adenylylcyclase inhibition or phospholipase stimulation. Thus, α₂-adrenergic receptors can couple to the p21(ras)-MAP kinase pathway via G(i), which may explain the mitogenic potential of α₂ agonists in certain cell types; together with previous results, these findings further suggest that activation of this pivotal signaling pathway may be a common event in the action of G(i)-coupled receptors.