© 2000 American Heart Association, Inc.
Editorial |
Cell Logic for Dual Coupling of a Single Class of Receptors to Gs and Gi Proteins
From the Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Md.
Correspondence to Rui-Ping Xiao, MD, PhD, Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail xiaor@grc.nia.nih.gov
Key Words: dual G protein coupling • ß-adrenergic receptor subtypes • cAMP compartmentalization • heart failure
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Introduction |
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Gprotein–coupled receptors mediate transmembrane signal transduction for a variety of hormones, neurotransmitters, chemokines, and synthetic ligands. It had been thought that a given receptor couples only to a single class of heterotrimeric G proteins to achieve signaling selectivity and specificity. As a model system of G protein–coupled receptors, ß-adrenergic receptor (ßAR) was believed to activate exclusively a Gs-adenylyl cyclase-cAMP-protein kinase A (PKA) signaling cascade. This doctrine, however, has been challenged by recent findings that, although seeming illogical, ß2AR dually couples to Gs and Gi proteins in rodent and canine hearts1 2 3 (for review, see Reference 4 ). In this issue of Circulation Research, Kilts et al5 present a solid study that provides additional evidence supporting a dual G protein coupling for ß2AR and extended the previous finding to several other Gs-coupled receptors in human heart.
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Gs and Gi Dichotomy |
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Early studies showed that stimulation of ß1AR, but not ß2AR, induces a relaxant effect,6 7 a hallmark of cAMP-dependent cardiac modulation. Moreover, ß2AR-induced augmentations in intracellular Ca2+ transient and contractility are apparently dissociated from cellular cAMP accumulation and PKA-mediated protein phosphorylation in rat ventricular myocytes, whereas the classic linear Gs-adenylyl cyclase-cAMP-PKA signaling cascade is corroborated for ß1AR stimulation.8 These findings provided the first clue that there are some substantial differences between ß1AR and ß2AR signaling pathways.
In search for answers to the anomalous behavior of cardiac
ß2AR stimulation, recent studies have revealed
dichotomous G protein coupling for native ß2AR
under physiological conditions. Disrupting
Gi
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