G(I)-MEDIATED ACTIVATION OF THE P21(RAS)-MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAY BY ALPHA(2)-ADRENERGIC RECEPTORS EXPRESSED IN FIBROBLASTS

The alpha2-adrenergic receptors are linked to inhibition of adenylylcy clase and, under certain circumstances, to stimulation of phospholipid hydrolysis via pertussis toxin-sensitive G proteins. Here we show tha t alpha2-adrenergic receptors can couple to an alternative signaling p athway. When expressed in Rat-1 cells, stimulation of the alpha2A rece ptor, which couples to G(i2) and G(i3), causes rapid, transient activa tion of the protooncogene product p21ras as measured by an increase in the amount of bound GTP. Furthermore, alpha2A receptor stimulation ca uses rapid phosphorylation of the p42 mitogen-activated protein (MAP) kinase. Pertussis toxin completely inhibits both p21ras activation and MAP kinase phosphorylation, but both responses appear to be independe nt of adenylylcyclase inhibition or phospholipase stimulation. Thus, a lpha2-adrenergic receptors can couple to the p21ras-MAP kinase pathway via G(i), which may explain the mitogenic potential of alpha2 agonist s in certain cell types; together with previous results, these finding s further suggest that activation of this pivotal signaling pathway ma y be a common event in the action of G(i)-coupled receptors.