Many of the G-protein-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^,,,. For example, although most of the actions of the prototype β₂-adrenergic receptor are mediated through G_s proteins and the cyclic-AMP-dependent protein kinase (PKA) system^,, β-adrenergic receptors can also couple to G_i proteins^,. 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 β₂-adrenergic receptor is mediated by the βγ 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 β₂-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, the enzyme that generates cAMP, but not MAP kinase. Our results demonstrate that a mechanism previously shown to mediate uncoupling of the β₂-adrenergic receptor from G_s and thus heterologous desensitization (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.