ß-Adrenergic Signaling in the Heart: Dual Coupling of the ß₂-Adrenergic Receptor to G_s and G_i Proteins

Rui-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

Abstract: ß-adrenergic receptor (AR) subtypes are archetypical members of the G protein-coupled receptor (GPCR) superfamily. Whereas both ß₁AR and ß₂AR stimulate the classic G_s-adenylyl cyclase-3',5'-adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling cascade, ß₂AR couples to both G_s and G_i proteins, activating bifurcated signaling pathways. In the heart, dual coupling of the ß₂AR 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 Ca²⁺ channels) and bypassing cytoplasmic target proteins (such as phospholamban and myofilament contractile proteins). More important, the ß₂AR-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, Gß, phosphoinositide 3-kinase, and Akt. Furthermore, cardiac-specific transgenic overexpression of ßAR 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 ßAR 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 ß₂AR may provide catecholamine-dependent inotropic support without cardiotoxic consequences, which might have beneficial effects in the failing heart.

Citation:
R.-P. Xiao, ß-Adrenergic Signaling in the Heart: Dual Coupling of the ß₂-Adrenergic Receptor to G_s and G_i Proteins. Science's STKE (2001), http://stke.sciencemag.org/cgi/content/full/OC_sigtrans;2001/104/re15.

© 2001 American Association for the Advancement of Science

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