Cell logic for dual coupling of a single class of receptors to G(s) and G(i) proteins.

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, b-adrenergic receptor (bAR) 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, b2AR dually couples to Gs and Gi proteins in rodent and canine hearts1–3 (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 b2AR and extended the previous finding to several other Gs-coupled receptors in human heart.