β-Adrenergic Signaling in the Heart: Dual Coupling of the β2-Adrenergic Receptor to Gs and Gi Proteins

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Science's STKE  16 Oct 2001:
Vol. 2001, Issue 104, pp. re15
DOI: 10.1126/stke.2001.104.re15

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G protein-coupled receptors (GPCRs) constitute the largest class of cell surface signaling molecules in eukaryotes and in some prokaryotes. By activating their cognate heterotrimeric guanosine triphosphate (GTP) binding proteins (G proteins), GPCRs transduce stimulatory or inhibitory signals for a wide array of endogenous hormones and neurotransmitters, and ambient physical and chemical stimuli, as well as exogenous therapeutic reagents. β-adrenergic receptors (βARs) are archetypical members of the GPCR superfamily. There are, at least, both β1AR and β2AR present in heart muscle cells. Whereas both βAR subtypes stimulate the classic Gs-adenylyl cyclase-3′,5′-adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling cascade, β2AR can activate bifurcated signaling pathways through Gs and Gi proteins. Because of their distinct G protein coupling, these βAR subtypes fulfill distinct, sometimes even opposite, physiological and pathological roles. Specifically, in the heart, whereas β1AR-generated cAMP signal can broadcast throughout the cell, the β2AR-stimulated cAMP signal is spatially and functionally compartmentalized to subsurface membrane microdomains by the concurrent Gi activation, thus selectively affecting plasma membrane effectors (such as L-type Ca2+ channels) and bypassing cytoplasmic regulatory proteins (such as phospholamban and myofilaments). Of potentially greater importance, the β2AR-to-Gi pathway also delivers a powerful cardiac protective signal. As a consequence, β1AR and β2AR exhibit opposing effects on heart cell survival: β1AR activation can promote programmed heart cell death (apoptosis); in sharp contrast, β2AR activation can protect heart cells from a wide range of assaulting factors, including enhanced β1AR stimulation, hypoxia, and reactive oxygen species. The β2AR survival pathway sequentially involves Gi, Gβγ, phosphoinositide 3-kinase (PI3K), and Akt. Furthermore, in vivo overexpression of β1AR, but not β2AR, induces heart muscle cell hypertrophy and heart failure in transgenic mouse models. These findings indicate that the differential G protein coupling, to a large extent, accounts for the distinctly different physiological and pathological roles in the heart for β2AR versus those of β1AR. The delicate balance of Gs and Gi signaling in space and time might be crucial to normal cellular functions, whereas an imbalance may have important pathophysiological relevance and clinical implications. For instance, selective activation of cardiac β2AR may provide catecholamine-dependent inotropic support without cardiotoxic consequences, which might have beneficial effects in the failing heart.