β2-adrenergic and several other G protein-coupled receptors in human atrial membranes activate both Gs and Gi

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