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Abstract:
ß-adrenergic receptor (AR) subtypes are archetypicalmembers of the G protein-coupled receptor (GPCR) superfamily.Whereas both ß1AR and ß2AR stimulate theclassic Gs-adenylyl cyclase-3',5'-adenosine monophosphate (cAMP)-proteinkinase A (PKA) signaling cascade, ß2AR couples toboth Gs and Gi proteins, activating bifurcated signaling pathways.In the heart, dual coupling of the ß2AR to Gs andGi results in compartmentalization of the Gs-stimulated cAMPsignal, thus selectively affecting plasma membrane effectors(such as L-type Ca2+ channels) and bypassing cytoplasmic targetproteins (such as phospholamban and myofilament contractileproteins). More important, the ß2AR-to-Gi branch deliversa powerful cell survival signal that counters apoptosis inducedby the concurrent Gs-mediated signal or by a wide range of assaultingfactors. This survival pathway sequentially involves Gi, Gß,phosphoinositide 3-kinase, and Akt. Furthermore, cardiac-specifictransgenic overexpression of ßAR subtypes in miceresults in distinctly different phenotypes in terms of the likelihoodof cardiac hypertrophy and heart failure. These findings indicatethat stimulation of the two ßAR subtypes activatesoverlapping, but different, sets of signal transduction mechanisms,and fulfills distinct or even opposing physiological and pathophysiologicalroles. Because of these differences, selective activation ofcardiac ß2AR may provide catecholamine-dependent inotropicsupport without cardiotoxic consequences, which might have beneficialeffects in the failing heart.
Citation:
R.-P. Xiao, ß-Adrenergic Signaling in the Heart: Dual Coupling of the ß2-Adrenergic Receptor to Gs and Gi Proteins. Science's STKE (2001), http://stke.sciencemag.org/cgi/content/full/OC_sigtrans;2001/104/re15.
Citation: R.-P. Xiao, ß-Adrenergic Signaling in the Heart: Dual Coupling of the ß2-Adrenergic Receptor to Gs and Gi Proteins. Sci. STKE2001, re15 (2001).
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, 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.
