© 1999 American Heart Association, Inc.
Original Contribution |
Coupling of ß2-Adrenoceptor to Gi Proteins and Its Physiological Relevance in Murine Cardiac Myocytes
From the Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging (R.-P.X., Y.-Y.Z., H.C., E.G.L.), Baltimore, Md; Institute of Developmental Biology (P.A.), Russian Academy of Sciences, Moscow, Russia; Department of Surgery (S.A.A., W.J.K.), Department of Medicine and Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, NC; and Abteilung Allgemeine Pharmakologie, Universitats-Krankenhaus Eppendorf (T.E.), Hamburg, Germany.
Correspondence to Rui-Ping Xiao, MD, PhD, Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail Xiaor{at}GRC.NIA.NIH.Gov
Abstract—Transgenic mouse models
have been developed to manipulate ß-adrenergic receptor (ßAR)
signal transduction. Although several of these models have altered
ßAR subtypes, the specific functional sequelae of ßAR stimulation
in murine heart, particularly those of ß2-adrenergic
receptor (ß2AR) stimulation, have not been characterized.
In the present study, we investigated effects of ß2AR
stimulation on contraction, [Ca2+]i
transient, and L-type Ca2+ currents
(ICa) in single ventricular
myocytes isolated from transgenic mice overexpressing human
ß2AR (TG4 mice) and wild-type (WT) littermates. Baseline
contractility of TG4 heart cells was increased by
3-fold relative to WT controls as a result of the presence of
spontaneous ß2AR activation. In contrast,
ß2AR stimulation by zinterol or isoproterenol plus a
selective ß1-adrenergic receptor (ß1AR)
antagonist CGP 20712A failed to enhance the
contractility in TG4 myocytes, and more surprisingly,
ß2AR stimulation was also ineffective in increasing
contractility in WT myocytes. Pertussis toxin (PTX)
treatment fully rescued the ICa,
[Ca2+]i, and contractile responses to
ß2AR agonists in both WT and TG4 cells. The PTX-rescued
murine cardiac ß2AR response is mediated by
cAMP-dependent mechanisms, because it was totally blocked by the
inhibitory cAMP analog Rp-cAMPS. These results suggest that
PTX-sensitive G proteins are responsible for the unresponsiveness of
mouse heart to agonist-induced ß2AR stimulation. This was
further corroborated by an increased incorporation of the photoreactive
GTP analog [
-32P]GTP azidoanilide into 
subunits of
Gi2 and Gi3 after ß2AR
stimulation by zinterol or isoproterenol plus the ß1AR
blocker CGP 20712A. This effect to activate Gi
proteins was abolished by a selective ß2AR blocker ICI
118,551 or by PTX treatment. Thus, we conclude that (1)
ß2ARs in murine cardiac myocytes couple to concurrent
Gs and Gi signaling, resulting in null
inotropic response, unless the Gi signaling is inhibited;
(2) as a special case, the lack of cardiac contractile response to
ß2AR agonists in TG4 mice is not due to a saturation of
cell contractility or of the cAMP signaling cascade but
rather to an activation of ß2AR-coupled Gi
proteins; and (3) spontaneous ß2AR activation may differ
from agonist-stimulated ß2AR signaling.
Key Words: ß2-adrenergic receptor • inhibitory G protein • cardiac contractility • L-type Ca2+ current • mice, transgenic
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M. Jain, C. C. Lim, K. Nagata, V. M. Davis, D. S. Milstone, R. Liao, and R. M. Mortensen Targeted inactivation of G{alpha}i does not alter cardiac function or {beta}-adrenergic sensitivity Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H569 - H575. [Abstract] [Full Text] [PDF]
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M. Flesch, S. Ettelbruck, S. Rosenkranz, C. Maack, B. Cremers, K.-D. Schluter, O. Zolk, and M. Bohm Differential effects of carvedilol and metoprolol on isoprenaline-induced changes in {beta}-adrenoceptor density and systolic function in rat cardiac myocytes Cardiovasc Res, February 1, 2001; 49(2): 371 - 380. [Abstract] [Full Text] [PDF]
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A. Chesley, M. S. Lundberg, T. Asai, R.-P. Xiao, S. Ohtani, E. G. Lakatta, and M. T. Crow The {beta}2-Adrenergic Receptor Delivers an Antiapoptotic Signal to Cardiac Myocytes Through Gi-Dependent Coupling to Phosphatidylinositol 3'-Kinase Circ. Res., December 8, 2000; 87(12): 1172 - 1179. [Abstract] [Full Text] [PDF]
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Y.-Y. Zhou, D. Yang, W.-Z. Zhu, S.-J. Zhang, D.-J. Wang, D. K. Rohrer, E. Devic, B. K. Kobilka, E. G. Lakatta, H. Cheng, et al. Spontaneous Activation of beta 2- but Not beta 1-Adrenoceptors Expressed in Cardiac Myocytes from beta 1beta 2 Double Knockout Mice Mol. Pharmacol., November 1, 2000; 58(5): 887 - 894. [Abstract] [Full Text]
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K. Wenzel-Seifert and R. Seifert Molecular Analysis of beta 2-Adrenoceptor Coupling to Gs-, Gi-, and Gq-Proteins Mol. Pharmacol., November 1, 2000; 58(5): 954 - 966. [Abstract] [Full Text]
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X.-J. Du, X.-M. Gao, G. L. Jennings, A. M. Dart, and E. A. Woodcock Preserved ventricular contractility in infarcted mouse heart overexpressing beta 2-adrenergic receptors Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2456 - H2463. [Abstract] [Full Text] [PDF]
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R.-P. Xiao Cell Logic for Dual Coupling of a Single Class of Receptors to Gs and Gi Proteins Circ. Res., October 13, 2000; 87(8): 635 - 637. [Full Text] [PDF]
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J. D. Kilts, M. A. Gerhardt, M. D. Richardson, G. Sreeram, G. B. Mackensen, H. P. Grocott, W. D. White, R. D. Davis, M. F. Newman, J. G. Reves, et al. {beta}2-Adrenergic and Several Other G Protein-Coupled Receptors in Human Atrial Membranes Activate Both Gs and Gi Circ. Res., October 13, 2000; 87(8): 705 - 709. [Abstract] [Full Text] [PDF]
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I. H. Derweesh, M. A. Wheeler, and R. M. Weiss Alterations in G-Proteins and beta -Adrenergic Responsive Adenylyl Cyclase in Rat Urinary Bladder during Aging J. Pharmacol. Exp. Ther., September 1, 2000; 294(3): 969 - 974. [Abstract] [Full Text]
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Z. Nagykaldi, D. Kem, R. Lazzara, and B. Szabo Conditioning of beta 1-adrenoceptor effect via beta 2-subtype on L-type Ca2+ current in canine ventricular myocytes Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1329 - H1337. [Abstract] [Full Text] [PDF]
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Y. G. Wang, A. M Samarel, and S. L Lipsius Laminin binding to {beta}1-integrins selectively alters {beta}1- and {beta}2-adrenoceptor signalling in cat atrial myocytes J. Physiol., August 15, 2000; 527(1): 3 - 9. [Abstract] [Full Text] [PDF]
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M. Zaugg, W. Xu, E. Lucchinetti, S. A. Shafiq, N. Z. Jamali, and M. A. Q. Siddiqui {beta}-Adrenergic Receptor Subtypes Differentially Affect Apoptosis in Adult Rat Ventricular Myocytes Circulation, July 18, 2000; 102(3): 344 - 350. [Abstract] [Full Text] [PDF]
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Y.-Y. Zhou, S.-Q. Wang, W.-Z. Zhu, A. Chruscinski, B. K. Kobilka, B. Ziman, S. Wang, E. G. Lakatta, H. Cheng, and R.-P. Xiao Culture and adenoviral infection of adult mouse cardiac myocytes: methods for cellular genetic physiology Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H429 - H436. [Abstract] [Full Text] [PDF]
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 I. Kouchi, O. Zolk, F. Jockenhovel, G. Itter, W. Linz, B. Cremers, and M. Bohm Increase in Gi{alpha} Protein Accompanies Progression of Post-Infarction Remodeling in Hypertensive Cardiomyopathy Hypertension, July 1, 2000; 36(1): 42 - 47. [Abstract] [Full Text] [PDF]
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H. K. Ranu, J. C. W. Mak, P. J. Barnes, and S. E. Harding Gi-dependent suppression of beta 1-adrenoceptor effects in ventricular myocytes from NE-treated guinea pigs Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1807 - H1814. [Abstract] [Full Text] [PDF]
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A. Sabri, E. Pak, S. A. Alcott, B. A. Wilson, and S. F. Steinberg Coupling Function of Endogenous {alpha}1- and {beta}-Adrenergic Receptors in Mouse Cardiomyocytes Circ. Res., May 26, 2000; 86(10): 1047 - 1053. [Abstract] [Full Text] [PDF]
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R. J. Lefkowitz, H. A. Rockman, and W. J. Koch Catecholamines, Cardiac {beta}-Adrenergic Receptors, and Heart Failure Circulation, April 11, 2000; 101(14): 1634 - 1637. [Full Text] [PDF]
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K. Singh, C. Communal, D. B. Sawyer, and W. S. Colucci Adrenergic regulation of myocardial apoptosis Cardiovasc Res, February 1, 2000; 45(3): 713 - 719. [Abstract] [Full Text] [PDF]
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J. L. Leaney, G. Milligan, and A. Tinker The G Protein alpha Subunit Has a Key Role in Determining the Specificity of Coupling to, but Not the Activation of, G Protein-gated Inwardly Rectifying K+ Channels J. Biol. Chem., January 14, 2000; 275(2): 921 - 929. [Abstract] [Full Text] [PDF]
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X.-J. Du, D. J. Autelitano, R. J. Dilley, B. Wang, A. M. Dart, and E. A. Woodcock {beta}2-Adrenergic Receptor Overexpression Exacerbates Development of Heart Failure After Aortic Stenosis Circulation, January 4, 2000; 101(1): 71 - 77. [Abstract] [Full Text] [PDF]
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 O.-E. Brodde and M. C. Michel Adrenergic and Muscarinic Receptors in the Human Heart Pharmacol. Rev., December 1, 1999; 51(4): 651 - 690. [Abstract] [Full Text] [PDF]
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Y.-Y. Zhou, L.-S. Song, E. G Lakatta, R.-P. Xiao, and H. Cheng Constitutive {beta}2-adrenergic signalling enhances sarcoplasmic reticulum Ca2+ cycling to augment contraction in mouse heart J. Physiol., December 1, 1999; 521(2): 351 - 361. [Abstract] [Full Text] [PDF]
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C. Communal, K. Singh, D. B. Sawyer, and W. S. Colucci Opposing Effects of {beta}1- and {beta}2-Adrenergic Receptors on Cardiac Myocyte Apoptosis : Role of a Pertussis Toxin-Sensitive G Protein Circulation, November 30, 1999; 100(22): 2210 - 2212. [Abstract] [Full Text] [PDF]
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H. R. Cross, C. Steenbergen, R. J. Lefkowitz, W. J. Koch, and E. Murphy Overexpression of the Cardiac {beta}2-Adrenergic Receptor and Expression of a {beta}-Adrenergic Receptor Kinase-1 ({beta}ARK1) Inhibitor Both Increase Myocardial Contractility but Have Differential Effects on Susceptibility to Ischemic Injury Circ. Res., November 26, 1999; 85(11): 1077 - 1084. [Abstract] [Full Text] [PDF]
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R.-P. Xiao, H. Cheng, Y.-Y. Zhou, M. Kuschel, and E. G. Lakatta Recent Advances in Cardiac {beta}2-Adrenergic Signal Transduction Circ. Res., November 26, 1999; 85(11): 1092 - 1100. [Abstract] [Full Text] [PDF]
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 J. J. Hunter and K. R. Chien Signaling Pathways for Cardiac Hypertrophy and Failure N. Engl. J. Med., October 21, 1999; 341(17): 1276 - 1283. [Full Text] [PDF]
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Y.-Y. Zhou, H. Cheng, L.-S. Song, D. Wang, E. G. Lakatta, and R.-P. Xiao Spontaneous beta 2-Adrenergic Signaling Fails To Modulate L-Type Ca2+ Current in Mouse Ventricular Myocytes Mol. Pharmacol., September 1, 1999; 56(3): 485 - 493. [Abstract] [Full Text]
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A. M. Feldman and C. McTiernan New Insight Into the Role of Enhanced Adrenergic Receptor-Effector Coupling in the Heart Circulation, August 10, 1999; 100(6): 579 - 582. [Full Text] [PDF]
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M. Kuschel, Y.-Y. Zhou, H. Cheng, S.-J. Zhang, Y. Chen, E. G. Lakatta, and R.-P. Xiao Gi Protein-mediated Functional Compartmentalization of Cardiac beta 2-Adrenergic Signaling J. Biol. Chem., July 30, 1999; 274(31): 22048 - 22052. [Abstract] [Full Text] [PDF]
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M. Kuschel, Y.-Y. Zhou, H. A. Spurgeon, S. Bartel, P. Karczewski, S.-J. Zhang, E.-G. Krause, E. G. Lakatta, and R.-P. Xiao ß2-Adrenergic cAMP Signaling Is Uncoupled From Phosphorylation of Cytoplasmic Proteins in Canine Heart Circulation, May 11, 1999; 99(18): 2458 - 2465. [Abstract] [Full Text] [PDF]
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M. Zheng, S.-J. Zhang, W.-Z. Zhu, B. Ziman, B. K. Kobilka, and R.-P. Xiao beta 2-Adrenergic Receptor-induced p38 MAPK Activation Is Mediated by Protein Kinase A Rather than by Gi or Gbeta gamma in Adult Mouse Cardiomyocytes J. Biol. Chem., December 15, 2000; 275(51): 40635 - 40640. [Abstract] [Full Text] [PDF]
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M.-C. Wellner-Kienitz, K. Bender, and L. Pott Overexpression of beta 1 and beta 2 Adrenergic Receptors in Rat Atrial Myocytes. DIFFERENTIAL COUPLING TO G PROTEIN-GATED INWARD RECTIFIER K+ CHANNELS VIA Gs AND Gi/o J. Biol. Chem., September 28, 2001; 276(40): 37347 - 37354. [Abstract] [Full Text] [PDF]
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S.-J. Zhang, H. Cheng, Y.-Y. Zhou, D.-J. Wang, W. Zhu, B. Ziman, H. Spurgoen, R. J. Lefkowitz, E. G. Lakatta, W. J. Koch, et al. Inhibition of Spontaneous beta 2-Adrenergic Activation Rescues beta 1-Adrenergic Contractile Response in Cardiomyocytes Overexpressing beta 2-Adrenoceptor J. Biol. Chem., July 7, 2000; 275(28): 21773 - 21779. [Abstract] [Full Text] [PDF]
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C. Communal, W. S. Colucci, and K. Singh p38 Mitogen-activated Protein Kinase Pathway Protects Adult Rat Ventricular Myocytes against beta -Adrenergic Receptor-stimulated Apoptosis. EVIDENCE FOR Gi-DEPENDENT ACTIVATION J. Biol. Chem., June 16, 2000; 275(25): 19395 - 19400. [Abstract] [Full Text] [PDF]
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