β 2 -Adrenergic and Several Other G Protein–Coupled Receptors in Human Atrial Membranes Activate Both G s and G i

Abstract —Cardiac G protein–coupled receptors that couple to Gα s and stimulate cAMP formation (eg, β-adrenergic, histamine, serotonin, and glucagon receptors) play a key role in cardiac inotropy. Recent studies in rodent cardiac myocytes and transfected cells have revealed that one of these receptors, the β 2 -adrenergic receptor (AR), also couples to the inhibitory G protein Gα i (activation of which inhibits cAMP formation). If β 2 ARs could be shown to couple to Gα i in the human heart, it would have important ramifications, because levels of Gα i increase with age and in failing human heart. Therefore, we investigated whether β 2 ARs in the human heart activate Gα i . By photoaffinity labeling human atrial membranes with [ 32 P]azidoanilido-GTP, followed by immunoprecipitation with antibodies specific for Gα i , we found that Gα i is activated by stimulation of β 2 ARs but not of β 1 ARs. In addition, we found that other Gα s -coupled receptors also couple to Gα i , including histamine, serotonin, and glucagon. When coupling of these receptors to Gα i is disrupted by pertussis toxin, their ability to stimulate adenylyl cyclase is enhanced. These data provide the first evidence that β 2 AR and many other Gα s -coupled receptors in human atrium also couple to Gα i and that abolishing the coupling of these receptors to Gα i increases the receptor-mediated adenylyl cyclase activity.