β2-Adrenergic and Several Other G Protein–Coupled Receptors in Human Atrial Membranes Activate Both Gsand Gi

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Abstract
—Cardiac G protein–coupled receptors that couple to Gαsand 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 β2-adrenergic receptor (AR), also couples to the inhibitory G protein Gαi(activation of which inhibits cAMP formation). If β2ARs could be shown to couple to Gαiin the human heart, it would have important ramifications, because levels of Gαiincrease with age and in failing human heart. Therefore, we investigated whether β2ARs in the human heart activate Gαi. By photoaffinity labeling human atrial membranes with [32P]azidoanilido-GTP, followed by immunoprecipitation with antibodies specific for Gαi, we found that Gαiis activated by stimulation of β2ARs but not of β1ARs. In addition, we found that other Gαs-coupled receptors also couple to Gαi, including histamine, serotonin, and glucagon. When coupling of these receptors to Gαiis disrupted by pertussis toxin, their ability to stimulate adenylyl cyclase is enhanced. These data provide the first evidence that β2AR and many other Gαs-coupled receptors in human atrium also couple to Gαiand that abolishing the coupling of these receptors to Gαiincreases the receptor-mediated adenylyl cyclase activity.

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