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Sci. STKE, 16 October 2001 REVIEWSß-Adrenergic Signaling in the Heart: Dual Coupling of the ß2-Adrenergic Receptor to Gs and Gi ProteinsRui-Ping Xiao Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, MD 21224, USA. Contact information: Tel: 410 558-8662, Fax: 410 558-8150, E-mail: XiaoR{at}grc.nia.nih.gov 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. ß-adrenergic receptors (ßARs) are archetypical members of the GPCR superfamily. There are, at least, both ß1AR and ß2AR present in heart muscle cells. Whereas both ßAR subtypes stimulate the classic Gs-adenylyl cyclase-3',5'-adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling cascade, ß2AR can activate bifurcated signaling pathways through Gs and Gi proteins. Because of their distinct G protein coupling, these ßAR subtypes fulfill distinct, sometimes even opposite, physiological and pathological roles. Specifically, in the heart, whereas ß1AR-generated cAMP signal can broadcast throughout the cell, the ß2AR-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 ß2AR-to-Gi pathway also delivers a powerful cardiac protective signal. As a consequence, ß1AR and ß2AR exhibit opposing effects on heart cell survival: ß1AR activation can promote programmed heart cell death (apoptosis); in sharp contrast, ß2AR activation can protect heart cells from a wide range of assaulting factors, including enhanced ß1AR stimulation, hypoxia, and reactive oxygen species. The ß2AR survival pathway sequentially involves Gi, Gß Citation: © 2001 American Association for the Advancement of Science
Citation: R.-P. Xiao, ß-Adrenergic Signaling in the Heart: Dual Coupling of the ß2-Adrenergic Receptor to Gs and Gi Proteins. Sci. STKE 2001, re15 (2001). The editors suggest the following Related Resources on Science sites:In Science Signaling
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, phosphoinositide 3-kinase (PI3K), and Akt. Furthermore, in vivo overexpression of ß1AR, but not ß2AR, 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 ß2AR versus those of ß1AR. 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 ß2AR may provide catecholamine-dependent inotropic support without cardiotoxic consequences, which might have beneficial effects in the failing heart.
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882
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