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Gprotein–coupled receptors mediate transmembrane signal transduction for a variety of hormones, neurotransmitters, chemokines, and synthetic ligands. It had been thought that a given receptor couples only to a single class of heterotrimeric G proteins to achieve signaling selectivity and specificity. As a model system of G protein–coupled receptors, β-adrenergic receptor (βAR) was believed to activate exclusively a Gs-adenylyl cyclase-cAMP-protein kinase A (PKA) signaling cascade. This doctrine, however, has been challenged by recent findings that, although seeming illogical, β2AR dually couples to Gs and Gi proteins in rodent and canine hearts1 2 3 (for review, see Reference 4 ). In this issue of Circulation Research , Kilts et al5 present a solid study that provides additional evidence supporting a dual G protein coupling for β2AR and extended the previous finding to several other Gs-coupled receptors in human heart.Early studies showed that stimulation of β1AR, but not β2AR, induces a relaxant effect,6 7 a hallmark of cAMP-dependent cardiac modulation. Moreover, β2AR-induced augmentations in intracellular Ca2+ transient and contractility are apparently dissociated from cellular cAMP accumulation and PKA-mediated protein phosphorylation in rat ventricular myocytes, whereas the classic linear Gs-adenylyl cyclase-cAMP-PKA signaling cascade is corroborated for β1AR stimulation.8 These findings provided the first clue that there are some substantial differences between β1AR and β2AR signaling pathways.In search for answers to the anomalous behavior of cardiac β2AR stimulation, recent studies have revealed dichotomous G protein coupling for native β2AR under physiological conditions. Disrupting Gi signaling by pertussis toxin (PTX)–mediated ribosylation enhances β2AR-induced contractile response in rat ventricular myocytes1 and unmasks the β2AR positive inotropic …

Cell Logic for Dual Coupling of a Single Class of Receptors to G s and G i Proteins

Cell Logic for Dual Coupling of a Single Class of Receptors to G _s and G _i Proteins