Many of the G-grotein-coupled receptors for hormones that bind to the cell surface can signal to the interior of the cell through several different classes of G protein(1-4). Far example, although most of the actions of the prototype beta(2)-adrenergic receptor are mediated through G(s) proteins and thr cyclic-AMP-dependent protein kinase (PKA) system(5,6), beta-adrenergis receptors can also couple to G(i) proteins(1,2). Here we investigate the mechanism that controls the specificity of this coupling. We show that in HEK293 cells, stimulation of mitogen-activated protein (MAP) kinase by the beta(2)-adrenergic receptor is mediated by the beta gamma subunits of pertussis-toxin-sensitive G proteins through a pathway involving the non-receptor tyrosine kinase c-Src and the G protein Ras, Activation of this pathway by the beta(2)-adrenergic receptor requires that the receptor be phosphorylated by PKA because it is blocked by H-89, an inhibitor of PKA. Additionally, a mutant of the receptor, which lacks the sites normally phosphorylated by PKA, can activate adenylyl cyclase(5), the enzyme that generates cAMP, but not MAP kinase. Our results demonstrate that a mechanism previously shown to mediate uncoupling of the beta(2)-adrenergic receptor from G(s) and thus heterologous desensitization(7) (PKA-mediated receptor phosphorylation), also serves to ’switch’ coupling of this receptor from G(s) to G(i) and initiate a new set of signalling events.