Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Sci. STKE, 16 October 2001
Vol. 2001, Issue 104, p. re15
β-Adrenergic Signaling in the Heart: Dual Coupling of the β2-Adrenergic Receptor to Gs and Gi Proteins
Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Baltimore, MD 21224, USA.
β-adrenergic receptor (AR) subtypes are archetypical members of the G protein-coupled receptor (GPCR) superfamily. Whereas both β1AR and β2AR stimulate the classic Gs-adenylyl cyclase-3',5'-adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling cascade, β2AR couples to both Gs and Gi proteins, activating bifurcated signaling pathways. In the heart, dual coupling of the β2AR to Gs and Gi results in compartmentalization of the Gs-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 β2AR-to-Gi branch delivers a powerful cell survival signal that counters apoptosis induced by the concurrent Gs-mediated signal or by a wide range of assaulting factors. This survival pathway sequentially involves Gi, Gβ, 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 β2AR may provide catecholamine-dependent inotropic support without cardiotoxic consequences, which might have beneficial effects in the failing heart.