β-Adrenergic Signaling in the Heart: Dual Coupling of the β 2 -Adrenergic Receptor to G s and G i Proteins

Abstract

β-adrenergic receptor (AR) subtypes are archetypical members of the G protein-coupled receptor (GPCR) superfamily. Whereas both β 1 AR and β 2 AR stimulate the classic G s -adenylyl cyclase-3′,5′-adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling cascade, β 2 AR couples to both G s and G i proteins, activating bifurcated signaling pathways. In the heart, dual coupling of the β 2 AR to G s and G i results in compartmentalization of the G s -stimulated cAMP signal, thus selectively affecting plasma membrane effectors (such as L-type Ca 2+ channels) and bypassing cytoplasmic target proteins (such as phospholamban and myofilament contractile proteins). More important, the β 2 AR-to-G i branch delivers a powerful cell survival signal that counters apoptosis induced by the concurrent G s -mediated signal or by a wide range of assaulting factors. This survival pathway sequentially involves G i , Gβγ, phosphoinositide 3-kinase, and Akt. Furthermore, cardiac-specific transgenic overexpression of βAR subtypes in mice results in distinctly different phenotypes in terms of the likelihood of cardiac hypertrophy and heart failure. These findings indicate that stimulation of the two βAR subtypes activates overlapping, but different, sets of signal transduction mechanisms, and fulfills distinct or even opposing physiological and pathophysiological roles. Because of these differences, selective activation of cardiac β 2 AR may provide catecholamine-dependent inotropic support without cardiotoxic consequences, which might have beneficial effects in the failing heart.