β 2 -Adrenergic and several other g protein-coupled receptors in human atrial membranes activate both G(s) and G(i)
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.
Kilts, JD; Gerhardt, MA; Richardson, MD; Sreeram, G; Mackensen, GB; Grocott, HP; White, WD; Davis, RD; Newman, MF; Reves, JG; Schwinn, DA; Kwatra, MM
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