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(Circulation Research. 2000;87:635.)
© 2000 American Heart Association, Inc.

Editorial

Cell Logic for Dual Coupling of a Single Class of Receptors to G_s and G_i Proteins

Rui-Ping Xiao

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{at}grc.nia.nih.gov

Key Words: dual G protein coupling • ß-adrenergic receptor subtypes • cAMP compartmentalization • heart failure

	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 G_s-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 G_s and G_i proteins in rodent and canine hearts^{1 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 G_s-coupled receptors in human heart.

	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 G_s-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 G_i signaling by pertussis toxin (PTX)–mediated ribosylation enhances ß₂AR-induced contractile response in rat ventricular myocytes¹ and unmasks the ß₂AR positive inotropic effect in mouse cardiac myocytes, in which G_i signaling fully negates ß₂AR/G_s-mediated contractile response.² More recently, photoaffinity labeling of G proteins with [³²P]-azidoanilido-GTP in conjunction with immunoprecipitation with antibodies specific for G_s and G_i provided direct biochemical evidence that ß₂AR activates both G_s and G_i (G_i2 and G_i3) signaling pathways, whereas ß₁AR selectively activates G_s in adult mouse cardiac myocytes.² By photolabeling human atrial membranes with [³²P]-azidoanilido-GTP, Kilts et al⁵ further demonstrated that cardiac G_i is activated by stimulation of ß₂AR and several other G_s-coupled receptors, including histamine, serotonin, and glucagon receptors. Thus, promiscuous G protein coupling seems to be a rather common pattern of receptor–G protein interaction in the physiological context, although this property is not shared by ß₁AR. These findings raise important questions regarding physiological and pathophysiological relevance of the additional G_i coupling of G_s-coupled receptors.

	Cell Logic for Receptor Coupling to More Than One G Protein

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Transmembrane receptor signaling is a complex biological process orchestrated by a myriad of receptors and G proteins. The interplay of G_s and G_i signaling has been clearly elucidated in crosstalk between different receptor families. For example, stimulation of G_i-coupled muscarinic receptors attenuates the positive inotropic effect of ßAR stimulation.^{9 10} However, cardiac ß₂AR and several other G_s-coupled receptors present intriguing cases in which crosstalk occurs between concurrent G_s and G_i signaling pathways originating from a single class of receptors. We are only beginning to appreciate the cellular logic behind the "one receptor, two G protein" signaling mechanism.

Although G_i is named for its inhibitory effect on adenylyl cyclase and activation of G_i may counteract the ability of G_s to stimulate adenylyl cyclase, as demonstrated by Kilts et al,⁵ it is noteworthy that the G_s and G_i interaction is not necessarily confined to the cyclase level.^{3 11} Counterintuitively, promiscuous G protein coupling may enhance, rather than compromise, the receptor signaling specificity. This point is perhaps best exemplified by ßAR subtype stimulation. In rodent and canine hearts, ß₁AR stimulation increases phosphorylation of phospholamban, which accelerates Ca²⁺ sequestration into the sarcoplasmic reticulum, resulting in accelerated cardiac relaxation,^{4 6 8 12} and increases phosphorylation of troponin I and C protein,¹² which reduces myofilament sensitivity to Ca²⁺. In contrast, ß₂AR stimulation modulates specifically L-type Ca²⁺ channels, bypassing the aforementioned intracellular regulatory proteins.^{3 6 8 12} In a direct approach involving on-cell patch-clamp recordings, it has been shown that ß₂AR stimulation modulates single L-type Ca²⁺ channel activity only in a local mode (agonist included in pipette solution) but not in a remote mode (agonist added to bathing solution outside the patch), whereas ß₁AR stimulation does so in either mode.¹³ G_i activation is essential to the spatial localization and effector selectivity of ß₂ AR signaling, because inhibiting G_i function with PTX permits a remote ß₂AR effect on L-type Ca²⁺ channels¹³ and a robust increase in phospholamban phosphorylation as well as a markedly accelerated relaxation in response to ß₂AR stimulation.³

Equally appealing, G_i activation may deliver G_s-independent signals through G_i and G_iß, further enriching receptor signaling diversity. For example, stimulation of the recombinant ß₂AR transiently expressed in HEK 293 cells activates both G_s and G_i; the latter increases the activity of mitogen-activated protein kinase,¹⁴ which plays an important role in regulating chronic cellular processes such as cell growth and cell death.

In principle, the aforementioned interplay between G_s and G_i signals could be conducted by two types of receptors coupled to G_s and G_i, respectively. In contrast to the "two receptor, two G protein" system, the beauty of the "one receptor, two G protein" design is that it ensures a proportional activation of the dual G protein signals and affords a spatial and temporal colocalization and coordination of these signals. The delicate balance of G_s and G_i signaling in space and time might be crucial to normal cellular functions.

	Pathophysiological Relevance

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Programmed cell death or apoptosis has been recently implicated as a consequence of cardiac ischemic/reperfusion injury, contributing to the transition from cardiac hypertrophy to decompensatory heart failure.^{15 16 17} In vivo and in vitro studies indicate that ß₁AR and ß₂AR exhibit distinctly different, even opposing, effects on cardiac myocyte apoptosis. In cultured adult rat cardiac myocytes, stimulation of ß₁AR, but not ß₂AR, induces myocyte apoptosis.¹⁸ Using a ß₁ß₂AR double knockout mouse model in conjunction with adenoviral gene transfer, we have created pure ßAR subtype experimental settings and found that ß₁AR stimulation markedly induces myocyte apoptosis. In contrast, ß₂AR stimulation activates concurrent apoptotic and survival signals mediated by G_i and G_s, respectively, with the G_i-mediated survival effect predominant (Zhu W-Z, Zheng M, Kolbilka BK, Xiao R-P, unpublished data, 2000). Moreover, activation of ß₂AR-coupled G_i protects cardiac myocytes from a range of apoptotic assaults, including hypoxia or reactive oxygen species–induced apoptosis (Chesley A, Ohtani S, Asai T, Xiao R-P, Lunberg MS, Lakatta EG, Crow MT, unpublished data, 2000).

Chronic stimulation of these ßAR subtypes in the heart also elicits strikingly different phenotypes in murine transgenic models. Overexpression of cardiac ß₁AR by 5- to 46-fold induces cardiac hypertrophy, apoptosis, and fibrosis within a few weeks after birth and heart failure within several months.^{19 20} Ironically, overexpression of cardiac ß₂AR by 100- to 200-fold does not induce hypertrophy or heart failure,^{21 22 23} at least up to the age of 1 year. However, overwhelming expression of ß₂AR (eg, 350- to 1000-fold) induces pathological phenotypes,^{22 23} perhaps caused by a mechanic and metabolic overload (markedly enhanced baseline adenylyl cyclase activity and cardiac contractility) due to spontaneous ß₂AR activation. Whether the distinct phenotypes of ß₂AR versus ß₁AR mouse transgenic models are related to their different G protein coupling merits further investigations.

Although activation of ß₂AR-coupled G_i protects cardiac myocytes against apoptosis, an imbalance of ß₂AR-initiated G_s and G_i signaling pathways may induce pathological consequences. Chronic heart failure in human and animal models is characterized by a diminished contractile response to ßAR stimulation,^{24 25 26 27 28 29} accompanied by a selective downregulation of ß₁AR (higher ß₂/ß₁ ratio)^{24 25 26 27} and an increase in the amount or activity of G_i proteins.^{27 28 29 30 31} In light of the G_s and G_i dichotomy, the upregulation of G_i may participate in the defect of ßAR inotropic effect in the decompensated failing heart. This idea is supported by recent observations that PTX treatment restores the diminished ßAR inotropic response in a rat myocardial infarction heart failure model³² and in myocytes from failing human hearts.³³

On the basis of these findings, we speculate that the selective downregulation of ß₁AR and the upregulation of ß₂AR/G_i signaling in functionally compensated hypertrophic heart or early stage of heart failure may represent a cardiac protective mechanism (eg, against myocyte apoptosis), which slows the progression of cardiomyopathy and contractile dysfunction. However, exaggerated ß₂AR/G_i signaling may blunt G_s-mediated contractile support, contributing to the phenotype of decompensated heart failure.

	Therapeutic Implications

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It has been highly controversial as to whether enhancing ßAR signaling is beneficial or deleterious for the failing heart. The prevalent view is that chronically increasing nonselective ßAR stimulation is toxic to the heart, because there is an inverse relationship between the plasma level of norepinephrine and the survival of patients with heart failure³⁴ and because ßAR blockade (eg, by ß₁AR antagonists bisoprolol and metoprolol or a nonselective ßAR blocker carvedilol) reduces both the morbidity and mortality in patients with heart failure.³⁵ However, the discovery of a new paradigm of ß₂AR signaling (ie, the dual G protein coupling), the opposing effects of stimulation of these ßAR subtypes on cardiomyocyte apoptosis, and the distinct phenotypes of cardiac-specific overexpression of ß₁AR versus ß₂AR underscore the necessity and importance of distinguishing ß₂AR signaling from that of ß₁AR in terms of their cardiac functional roles and therapeutic implications.

In our opinion, selectively enhancing ß₂AR signaling may provide a novel therapeutic strategy in the prevention and treatment of chronic heart failure. Indeed, crossing transgenic mice overexpressing cardiac ß₂AR at appropriate levels (eg, 30-fold) with transgenic mice overexpressing G_q not only improves the cardiac performance but also reverses hypertrophy in the G_q overexpression heart failure model,²² although extremely high levels of ß₂AR overexpression (eg, 350- to 1000-fold) fail to rescue the genetic mouse heart failure model.²² Additionally, the beneficial effect of ß₂AR stimulation in the context of heart failure is clearly supported by the analysis of polymorphisms of ß₂AR in chronic heart failure patients. The likelihood of earlier aggressive intervention or cardiac transplantation is significantly greater in heart failure patients with Ile164 polymorphism (a Thr to Ile switch at amino acid 164 with reduced ß₂AR signaling efficacy) relative to patients without the ß₂AR variant.³⁶

In summary, coupling of one receptor to more than one class of G proteins may represent a common property of many G_s-coupled receptors, rather than a unique quality of ß₂AR. The additional G_i coupling not only confers spatial and temporal control of G_s-stimulated signals, enhancing the receptor signaling specificity, but also enriches signaling diversity by delivering G_s-independent signals. The discovery of the G_s and G_i dichotomy reshapes our current understanding of receptor–G protein interactions in physiological systems. An imbalance of the concurrent G_s and G_i signals may have important pathophysiological relevance and clinic implications.

	Acknowledgments

 
I would like to thank Drs Edward G. Lakatta and Heping Cheng for critical discussions and comments.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

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