In many tissues, inwardly rectifying K channels are coupled to seven- helix receptors via the Gi/Go family of heterotrimeric G proteins. This activation proceeds at least partially via Gβγ subunits. These experiments test the hypothesis that Gβγ subunits activate the channel even if released from other classes of heterotrimeric G proteins. The G protein-gated K channel from rat atrium, KGA/GIRK1, was expressed in Xenopus oocytes with various receptors and G proteins. The β2-adrenergic receptor (β2AR), a Gs- linked receptor, activated large KGA currents when the α subunit, Gαs, was also overexpressed. Although augmented the coupling between β2AR and KGA, Gαs also inhibited the basal, agonist-independent activity of KGA. KGA currents stimulated via β2AR activated, deactivated, and desensitized more slowly than currents stimulated via Gi/Go-linked receptors. There was partial occlusion between currents stimulated via β2AR and the m2 muscarinic receptor (a Gi/Go-linked receptor), indicating some convergence in the mechanism of activation by these two receptors. Although stimulation of β2AR also activates adenylyl cyclase and protein kinase A, activation of KGA via β2AR is not mediated by this second messenger pathway, because direct elevation of intracellular cAMP levels had no effect on KGA currents. Experiments with other coexpressed G protein α and β subunits showed that (a) a constitutively active Gαs mutant did not suppress basal KGA currents and was only partially as effective as wild type Gαs in coupling β2AR to KGA, and (b) βγ subunits increased basal KGA currents. These results reinforce present concepts that βγ subunits activate KGA, and also suggest that βγ subunits may provide a link between KGA and receptors not previously known to couple to inward rectifiers.