Circulation Research. 2005;97:507-509
doi: 10.1161/01.RES.0000184615.56822.bd
doi: 10.1161/01.RES.0000184615.56822.bd
© 2005 American Heart Association, Inc.
Editorials |
The Enigma of ß2-Adrenergic Receptor Gi Signaling in the Heart
The Good, the Bad, and the Ugly
From the Laboratory of Cardiovascular Science (W.Z., X.Z., R.-P.X.), National Institute of Aging, National Institutes of Health, Baltimore, Md; and The Institute of Molecular Medicine (M.Z., R.-P.X.), Peking University, Beijing, China.
Correspondence to Rui-Ping Xiao, MD, PhD, Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224. E-mail xiaor{at}grc.nia.nih.gov
See related article, pages 566–573
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Introduction |
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 Top Introduction The "Good": Cardioprotection...The " Bad" or...The Cell Logic of...Potential Mechanisms Underlying...References |
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Four decades ago, it was thought that the cardiac ß-adrenergic receptor (AR) was ß1AR, the vascular/bronchial counterpart was ß2AR, and that ß2AR was either nonexistent or nonfunctional in myocardium.1 In the heart, stimulation of ß1AR leads to PKA-dependent phosphorylation of a set of Ca2+ regulatory proteins, including sarcolemmal L-type Ca2+ channels, sarcoplasmic reticulum (SR) Ca2+-release channels (ryanodine receptors), SR Ca2+-ATPase (SERCA) and its regulator phospholamban (PLB), and some myofilament proteins, resulting in positive inotropic, lusitropic, and chronotropic effects. However, over the past decade, compelling evidence has shown that the ß2AR subtype is expressed in the heart and its signaling and functionalities markedly differ from those evoked by the closely related ßAR subtype, the ß1AR. Unlike ß1AR, ß2AR couples dually to Gs and Gi proteins; the ß2AR-Gi signaling pathway plays a crucial role in cardioprotection against apoptotic death of myocytes in culture and in vivo (the "good"), while attenuating the ß2AR-Gs-mediated inotropic response (the "bad") (Figure).2 Now, in the current issue of Circulation Research, He et al revealed one "ugly" facet of the ß2AR-Gi signaling in a canine heart failure model.3 They demonstrated that in the failing heart, activation of ß2AR dampens the ability of ß1AR, the primary cardiac subtype, to stimulate ICa,L, thus resulting in an overall dysfunction of ßAR inotropic response in the failing heart (Figure).3 Specifically, the effect of ßAR stimulation with a nonselective agonist, isoproterenol (ISO), on ICa,L is strikingly diminished in cardiomyocytes from canine failing heart, but can be revived by disruption of Gi function with pertussis toxin (PTX) or ß2AR blockade with ICI 118 551.3 These findings highlight that an alteration in the status of the ß2AR-Gi coupling can dictate the overall outcome of cardiac ßAR signaling under some pathological circumstances. Thus, this enigmatic, multifaceted ß2AR-Gi signaling pathway might bear important pathogenic and therapeutic implications.
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The "Good": Cardioprotection Induced by Sustained ß2AR Stimulation |
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TopIntroductionThe "Good": Cardioprotection...The " Bad" or...The Cell Logic of...Potential Mechanisms Underlying...References |
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A large body of evidence gleaned from pharmacological and mouse genetic studies has revealed opposing contributions of sustained ß1AR and ß2AR stimulation in regulating the fate of cardiomyocytes. Whereas sustained ß1AR stimulation promotes apoptotic death of cardiomyocytes, sustained stimulation of ß2AR protects myocytes against a wide range of apoptotic insults. For instance, agonist-induced ß2AR stimulation prevents catecholamine-, hypoxia-, or reactive oxygen species (ROS)-induced apoptotic death in both neonatal and adult rat cardiomyocytes.4–6 Moreover, in adult mice lacking the native ß2AR, stimulation of the native ß1AR by catecholamine causes overtly exaggerated cardiomyopathy, myocyte apoptosis, and more severe heart failure relative to wild-type control animals.7 In contrast, selective activation of ß2AR by fenoterol for 8 weeks exerts a clear antiapoptotic effect and improves cardiac performance in a myocardial infarction–induced rat heart failure model.8 These in vivo studies have provided evidence that ß2AR stimulation exerts a cardiac protective effect in response to elevated circulating catecholamine levels or myocardial infarction.
The cardiac protective effect of persistent ß2AR signaling is largely mediated by ß2AR-Gi coupling, which, in turn, activates a cell survival pathway sequentially involving Giß
, PI3K, and Akt. First, ß2AR blockade enhances ß1AR-induced apoptosis in cultured adult rat myocytes in a PTX-sensitive manner, suggesting the ß2AR protective effect is Gi-dependent.4 Second, ß2AR, but not ß1AR, activates a Gi-Gß-PI3K-Akt cell survival signaling pathway6,9, and inhibition of this pathway abolishes the ability of ß2AR to block hypoxia- and ROS-induced myocyte apoptosis.6 Thus, the ß2AR-Gi- Gß-PI3K-Akt signaling cascade not only counteracts ßAR-induced apoptosis and but also protects cardiomyocytes against other apoptotic stimuli.
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The " Bad" or "Ugly": ß2AR-coupled Gi Negates ß1AR- and ß2AR-Mediated Contractile Support in the Failing Heart |
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TopIntroductionThe "Good": Cardioprotection...The " Bad" or...The Cell Logic of...Potential Mechanisms Underlying...References |
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Although beneficial in terms of cardiac protection, the ß2AR protective effect comes at the cost of compromised contractile support. Previous studies have demonstrated that the ß2AR-Gi functionally restricts the ß2AR-Gs–mediated cAMP/PKA signaling to subsarcolemmal microdomain in the vicinity of L-type Ca2+ channels, thus preventing the Gs-PKA mediated phosphorylation of some key target proteins in SR membrane and intracellular contractile myofilaments, blunting the positive inotropic and lusitropic effects.10–13 Activation of PI3K, an important downstream event of the ß2AR-Gi signaling, confines and minimizes the concurrent ß2AR-Gs–evoked cAMP/PKA signaling.14 In the failing heart, an upregulation of Gi15 and a selective downregulation of ß1AR16 are often associated with enhanced ß2AR-Gi signaling and reduced myocardial contractile response to both ß1AR and ß2AR stimulation. Importantly, inhibition of the Gi signaling pathway with PTX restores the diminished ßAR inotropic response in a variety of heart failure models, including a spontaneous hypertensive rat heart failure model,17 a myocardial infarction rat heart failure model,18 and myocytes from failing human hearts.19 Furthermore, in failing porcine and mouse hearts or cardiomyocytes, inhibition of ßAR-targeted PI3K, the major downstream mediator the Gi signaling, improves the contractile function of the failing myocardium.20,21 Now, He and colleagues demonstrate a cross-inhibition of ß1AR-mediated stimulation of ICa,L by the ß2AR-Gi signaling.3 Similarly, the ß2AR-Gi signaling largely inhibits ß1AR-induced positive inotropic effect in adult rat cardiomyocytes moderately overexpressing Na+/Ca2+ exchanger proteins.22 Collectively, these studies suggest that reinforcement of ß2AR-Gi signaling is a hallmark of the failing heart and is critically involved in heart failure–associated dysfunction or desensitization of both ßAR subtypes.
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The Cell Logic of Multifaceted ß2AR-Gi Signaling |
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TopIntroductionThe "Good": Cardioprotection...The " Bad" or...The Cell Logic of...Potential Mechanisms Underlying...References |
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At the first glance, inhibition of the ß1AR-mediated stimulation of ICa,L and, consequentially, the contractile response by ß2AR-coupled Gi might paint ß2AR stimulation as the "bad guy" in the context of heart failure. It is, however, noteworthy that sustained ß1AR stimulation induces myocyte apoptosis and positive inotropic effect mainly via PKA-independent stimulation of L-type Ca2+ channels and resultant activation of CaMKII in adult mouse and rat cardiomyocytes (Figure).23,24 Inhibition of ICa,L or CaMKII can effectively protect the cultured cardiomyocytes from ß1AR-induced apoptotic death.23 In contrast, overexpression of the L-type channel (
1C) causes severe cardiac hypertrophy and apoptosis.25 Recent in vivo studies have further confirmed that inhibition of CaMKII substantially prevents cardiac maladaptive remodeling from excessive ßAR stimulation and myocardial infarction and markedly improves cardiac function (Figure).26 In light of these observations, we envision that the inhibitory effect of the ß2AR-Gi signaling on ß1AR-mediated activation of ICa,L and resultant CaMKII may represent an intrinsic cardiac protective mechanism, acting as a "friend" rather than a "foe," to protect the heart against apoptosis and maladaptive remodeling in response to chronic catecholamine stimulation. Thus, the apparent "bad" or "ugly" behavior might be an overreaction of the defense mechanism; appropriately tipping the balance might be able to bring out the "good" nature of ß2AR-Gi signaling to benefit the struggling heart. |
Potential Mechanisms Underlying the Gi-Dependent Crosstalk of ßAR Subtypes |
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TopIntroductionThe "Good": Cardioprotection...The " Bad" or...The Cell Logic of...Potential Mechanisms Underlying...References |
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The exact mechanism underlying the cross-inhibition of ß1AR function by the ß2AR-Gi signaling remains elusive. There are several candidate mechanisms, including the ß2AR-Gi signaling–mediated direct suppression of adenylyl cyclase activity or activation of PI3K. With respect to the latter, it has been shown that activation of PI3K inhibits ICa,L in normal adult rat cardiomyocytes.27 More importantly, inhibition of membrane-targeted PI3K activity ameliorates cardiac dysfunction and improves survival in multiple heart failure models.20,21
Alternatively, we have recently demonstrated that ß1AR and ß2AR are able to form heterodimers in adult mouse cardiomyocytes and HEK 293 cells.28,29 Specifically, in cardiomyocytes, the heterodimeric receptors exhibit altered ligand binding profiles, enhanced signaling efficiency in regulating myocyte cAMP production and contractility, and suppressed ß2AR spontaneous activity in the absence of agonist stimulation, thus optimizing ß-adrenergic regulation of cardiac contractility (Figure).28 Interestingly, heterodimerization between ß1AR and ß2AR inhibits the agonist-promoted internalization of ß2AR and its ability to activate the Gi-ERK1/2 MAPK signaling pathway in HEK 293 cells.29 Similarly, whereas either ß2AR or ß3AR alone couples to both Gs and Gi proteins, the ß2AR-ß3AR heterodimer is unable to activate Gi signaling.30 Thus, alterations in the status of oligomerization of GPCRs from the same or different families may lead to changes in the selectivity and specificity of G protein coupling of those receptors, thereby altering their signaling and functional features, perhaps also raising important therapeutic considerations.
The heart failure–associated decrease in the ratio of ß1AR to ß2AR,3,16 in conjunction with changes in cardiomyocyte morphology and membrane integrity, might interfere with the heterodimerization of the remaining ßARs, thus allowing the ß2AR to better couple to Gi proteins. The enhanced Gi signaling inhibits ß1AR-mediated increases in ICa,L and contractility, perhaps most importantly, ameliorates ß1AR-evoked maladaptive remodeling and loss of cardiomyocytes (Figure). These hypotheses merit future investigation.
In summary, it is reasonable to speculate that the selective downregulation of ß1AR and the upregulation of ß2AR-coupled Gi signaling in the functionally compensated hypertrophied heart may represent salutary cardiac adaptation, which may protect myocytes against apoptosis and maladaptive remodeling and consequently slow the progression of cardiomyopathy and contractile dysfunction. However, exaggerated ß2AR-Gi signaling blunts the Gs-mediated stimulation of ICa,L and contractile support, thus contributing to the contractile defect of the failing heart despite of its antiapoptotic effect. Thus, restoration of the Yin and Yang balance of ß2AR-coupled Gi and Gs signaling cascades may open a novel therapeutic avenue for the treatment of heart failure.
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Acknowledgments |
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This work is supported by National Institutes of Health intramural research grant (to Z.W.Z., X.Z., and R.P.X.), and in part by Chinese National Key Project 973 (G2000056906) and Chinese Young Investigator Award (30225036). The authors thank Dr H. Cheng for critical comments and discussions.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionThe "Good": Cardioprotection...The " Bad" or...The Cell Logic of...Potential Mechanisms Underlying...References |
|---|
- Lands AM, Arnold A, Mcauliff JP, Luduena FP, Brown TG. Differentiation of receptor systems activated by sympathomimetic amines. Nature. 1967; 214: 596–598.
- Xiao RP, Zhu W, Zheng M, Bond R, Lakatta EG, Cheng H. Subtype-specific ß-adrenergic signaling pathways and their clinical implications. Trends Pharmacol Sci. 2004; 25: 358–365.[CrossRef][Medline] [Order article via Infotrieve]
- He JQ, Balijepalli RC, Haworth RA, Kamp TJ. Crosstalk of ß-adrenergic receptor subtypes through Gi blunts ß-adrenergic stimulation of L-type Ca2+ channels in canine heart failure. Circ Res. 2005; 97: 566–573.
[Abstract/Free Full Text] - Communal C, Singh K, Sawyer DB, Colucci WS. Opposing effects of ß1- and ß2-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis toxin-sensitive G protein. Circulation. 1999; 100: 2210–2212.
[Abstract/Free Full Text] - Zaugg M, Xu W, Lucchinetti E, Shafiq SA, Jamali NZ, Siddiqui MA. ß-adrenergic receptor subtypes differentially affect apoptosis in adult rat ventricular myocytes. Circulation. 2000; 102: 344–350.
[Abstract/Free Full Text] - Chesley A, Ohtani S, Asai T, Xiao RP, Lunberg MS, Lakatta EG, Crow MT. The ß2-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through Gi-dependent coupling to phosphatidylinositol 3'-kinase. Circ Res. 2000; 87: 1172–1179.
[Abstract/Free Full Text] - Patterson AJ, Zhu W, Chow A, Agrawal R, Kosek J, Xiao RP, Kobilka B. Protecting the myocardium: a role for the ß2-adrenergic receptor in the heart. Crit Care Med. 2004; 32: 1041–1048.[CrossRef][Medline] [Order article via Infotrieve]
- Ahmet I, Krawczyk M, Heller P, Moon C, Lakatta EG, Talan MI. Beneficial effects of chronic pharmacological manipulation of ß-adrenoreceptor subtype signaling in rodent dilated ischemic cardiomyopathy. Circulation. 2004; 110: 1083–1090.
[Abstract/Free Full Text] - Zhu WZ, Zheng M, Lefkowitz RJ, Koch WJ, Kobilka B, Xiao RP. Dual modulation of cell survival and cell death by ß2-adrenergic signaling in adult mouse cardiac myocytes. Proc Natl Acad Sci U S A. 2001; 98: 1607–1612.
[Abstract/Free Full Text] - Kuschel M, Zhou YY, Cheng H, Zhang SJ, Chen-Izu Y, Lakatta EG, Xiao RP. Gi protein-mediated functional compartmentalization of cardiac ß2-adrenergic signaling. J Biol Chem. 1999; 274: 22048–22052.
[Abstract/Free Full Text] - Chen-Izu Y, Xiao RP, Izu LT, Cheng H, Kuschel M, Spurgeon H, Lakatta EG. Gi-dependent localization of ß2-adrenergic receptor signaling to L-type Ca2+ channels. Biophys J. 2000; 79: 2547–2556.
[Abstract/Free Full Text] - Xiao RP, Ji X, Lakatta EG. Functional coupling of the ß2-adrenoceptor to a pertussis toxin-sensitive G protein in cardiac myocytes. Mol Pharmacol. 1995; 47: 322–329.[Abstract]
- Xiao RP, Avdonin P, Zhou YY, Cheng H, Akhter SA, Eschenhagen T, Lefkowitz RJ, Koch WJ, Lakatta EG. Coupling of ß2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes. Circ Res. 1999; 84: 43–52.
[Abstract/Free Full Text] - Jo SH, Leblais V, Wang PH, Crow MT, Xiao RP. Phosphatidylinositol 3-kinase functionally compartmentalizes the concurrent Gs signaling during ß2-adrenergic stimulation. Circ Res. 2002; 91: 46–53.
[Abstract/Free Full Text] - Eschenhagen T, Mende U, Nose M, Schmitz W, Scholz H, Haverich A, Hirt S, Doring V, Kalmar P, Hoppner W. Increased messenger RNA level of the inhibitory G protein alpha subunit Gia1 in human end-stage heart failure. Circ Res. 1992; 70: 688–696.
[Abstract/Free Full Text] - Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W, Rasmussen R, Zera P, Menlove R, Shah P, Jamieson S. ß1- and ß2-adrenergic receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective ß1-receptor down-regulation in heart failure. Circ Res. 1986; 59: 297–309.
[Abstract/Free Full Text] - Xiao RP, Zhang SJ, Chakir K, Avdonin P, Zhu W, Bond RA, Balke CW, Lakatta EG, Cheng H. Enhanced Gi signaling mediates the diminution of ß2-adrenergic contractile response in failing spontaneous hypertensive rat heart. Circulation. 2003; 108: 1633–1639.
[Abstract/Free Full Text] - Kompa AR, Gu XH, Evans BA, Summers RJ. Desensitization of cardiac ß-adrenoceptor signaling with heart failure produced by myocardial infarction in the rat. Evidence for the role of Gi but not Gs or phosphorylating proteins. J Mol Cell Cardiol. 1999; 31: 1185–1201.[CrossRef][Medline] [Order article via Infotrieve]
- Brown LA, Harding SE. The effect of pertussis toxin on ß-adrenoceptor responses in isolated cardiac myocytes from noradrenaline-treated guinea-pigs and patients with cardiac failure. Br J Pharmacol. 1992; 106: 115–122.[Medline] [Order article via Infotrieve]
- Perrino C, Naga Prasad SV, Schroder JN, Hata JA, Milano C, Rockman HA. Restoration of ß-adrenergic receptor signaling and contractile function in heart failure by disruption of the ßARK1/phosphoinositide 3-kinase complex. Circulation. 2005; 111: 2579–2587.
[Abstract/Free Full Text] - Perrino C, Naga Prasad SV, Patel M, Wolf MJ, Rockman HA. Targeted inhibition of ß-adrenergic receptor kinase-1-associated phosphoinositide-3 kinase activity preserves ß-adrenergic receptor signaling and prolongs survival in heart failure induced by calsequestrin overexpression. J Am Coll Cardiol. 2005; 45: 1862–1870.
[Abstract/Free Full Text] - Sato M, Gong H, Terracciano CMN, Ranu H, Harding SE. Loss of ß-adrenoceptor response in myocytes overexpressing the Na+/Ca2+-exchanger. J Mol Cell Cardiol. 2004; 36: 43–48.[CrossRef][Medline] [Order article via Infotrieve]
- Zhu WZ, Wang SQ, Chakir K, Kolbilka BK, Cheng H, Xiao RP. Linkage of ß1-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/Calmodulin Kinase II. J Clin Invest. 2003; 111: 617–625.[CrossRef][Medline] [Order article via Infotrieve]
- Wang W, Zhu W, Wang S, Yang D, Crow MT, Xiao RP, Cheng H. Sustained ß1-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway. Circ Res. 2004; 95: 798–806.
[Abstract/Free Full Text] - Muth JN, Bodi I, Lewis W, Varadi G, Schwartz A. A Ca2+-dependent transgenic model of cardiac hypertrophy: A role for protein kinase Calpha. Circulation. 2001; 103: 140–147.
[Abstract/Free Full Text] - Zhang R, Khoo MSC, Wu Y, Yang Y, Grueter CE, Ni G, Price EE Jr, Thiel W, Guatimosim S, Song LS, Madu EC, Shah AN, Vishnivetskaya TA, Atkinson JB, Gurevich VV, Salama G, Lederer WJ, Colbran RJ, Anderson ME. Calmodulin kinase II inhibition protects against structural heart disease. Nature Medicine. 2005; 11: 409–417.[CrossRef][Medline] [Order article via Infotrieve]
- Leblais V, Jo SH, Chakir K, Maltsev V, Zheng M, Crow MT, Wang W, Lakatta EG, Xiao RP. Phosphatidylinositol 3-kinase offsets cAMP-mediated positive inotropic effect via inhibiting Ca2+ influx in cardiomyocytes. Circ Res. 2004; 95: 1183–1190.
[Abstract/Free Full Text] - Zhu WZ, Chakir K, Zhang S, Yang D, Lavoie C, Bouvier M, Hébert TE, Lakatta EG, Cheng H, Xiao RP. Heterodimerization of ß1- and ß2-adrenergic receptor subtypes optimizes ß-adrenergic modulation of cardiac contractility. Circ Res. 2005; 97: 244–251.
[Abstract/Free Full Text] - Lavoie C, Mercier JF, Salahpour A, Umapathy D, Breit A, Villeneuve LR, Zhu WZ, Xiao RP, Lakatta EG, Bouvier M, Hebert TE. ß1/ß2-adrenergic receptor heterodimerization regulates ß2-adrenergic receptor internalization and ERK signaling efficacy. J Biol Chem. 2002; 277: 35402–35410.
[Abstract/Free Full Text] - Breit A, Lagace M, Bouvier M. Hetero-oligomerization between ß2- and ß3-adrenergic receptors generates a ß-adrenergic signaling unit with distinct functional properties. J Biol Chem. 2004; 279: 28756–28765.
[Abstract/Free Full Text]
Related Article:
- Crosstalk of ß-Adrenergic Receptor Subtypes Through Gi Blunts ß-Adrenergic Stimulation of L-Type Ca2+ Channels in Canine Heart Failure
- Jia-Qiang He, Ravi C. Balijepalli, Robert A. Haworth, and Timothy J. Kamp
Circ. Res. 2005 97: 566-573.[Abstract] [Full Text] [PDF]
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