Gi-mediated activation of the p21ras-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.