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• W2057029395 abstract "Cardiac G protein-coupled receptors that function through stimulatory G protein Gαs, such as β1- and β2-adrenergic receptors (β1ARs and β2ARs), play a key role in cardiac contractility. Recent data indicate that several Gαs-coupled receptors in heart also activate Gαi, including β2ARs (but not β1ARs). Coupling of cardiac β2ARs to Gαi inhibits adenylyl cyclase and opposes β1AR-mediated apoptosis. Dual coupling of β2AR to both Gαs and Gαi is likely to alter β2AR function in disease, such as congestive heart failure in which Gαi levels are increased. Indeed, heart failure is characterized by reduced responsiveness of βARs. Cardiac βAR-responsiveness is also decreased with aging. However, whether age increases cardiac Gαi has been controversial, with some studies reporting an increase and others reporting no change. The present study examines Gαi in left ventricular membranes from young and old Fisher 344 rats by employing a comprehensive battery of biochemical assays. Immunoblotting reveals significant increases with age in left ventricular Gαi2, but no changes in Gαi3, Gαo, Gαs, Gβ1, or Gβ2. Aging also increases ADP-ribosylation of pertussis toxin-sensitive G proteins. Consistent with these results, basal as well as receptor-mediated incorporation of photoaffinity label [32P]azidoanilido-GTP indicates higher amounts of Gαi2 in older left ventricular membranes. Moreover, both basal and receptor-mediated adenylyl cyclase activities are lower in left ventricular membranes from older rats, and disabling of Gαi with pertussis toxin increases both basal and receptor-stimulated adenylyl cyclase activity. Finally, age produces small but significant increases in muscarinic potency for the inhibition of both β1AR- and β2AR-stimulated adenylyl cyclase activity. The present study establishes that Gαi2 increases with age and provides data indicating that this increase dampens adenylyl cyclase activity. Cardiac G protein-coupled receptors that function through stimulatory G protein Gαs, such as β1- and β2-adrenergic receptors (β1ARs and β2ARs), play a key role in cardiac contractility. Recent data indicate that several Gαs-coupled receptors in heart also activate Gαi, including β2ARs (but not β1ARs). Coupling of cardiac β2ARs to Gαi inhibits adenylyl cyclase and opposes β1AR-mediated apoptosis. Dual coupling of β2AR to both Gαs and Gαi is likely to alter β2AR function in disease, such as congestive heart failure in which Gαi levels are increased. Indeed, heart failure is characterized by reduced responsiveness of βARs. Cardiac βAR-responsiveness is also decreased with aging. However, whether age increases cardiac Gαi has been controversial, with some studies reporting an increase and others reporting no change. The present study examines Gαi in left ventricular membranes from young and old Fisher 344 rats by employing a comprehensive battery of biochemical assays. Immunoblotting reveals significant increases with age in left ventricular Gαi2, but no changes in Gαi3, Gαo, Gαs, Gβ1, or Gβ2. Aging also increases ADP-ribosylation of pertussis toxin-sensitive G proteins. Consistent with these results, basal as well as receptor-mediated incorporation of photoaffinity label [32P]azidoanilido-GTP indicates higher amounts of Gαi2 in older left ventricular membranes. Moreover, both basal and receptor-mediated adenylyl cyclase activities are lower in left ventricular membranes from older rats, and disabling of Gαi with pertussis toxin increases both basal and receptor-stimulated adenylyl cyclase activity. Finally, age produces small but significant increases in muscarinic potency for the inhibition of both β1AR- and β2AR-stimulated adenylyl cyclase activity. The present study establishes that Gαi2 increases with age and provides data indicating that this increase dampens adenylyl cyclase activity. G protein-coupled receptor β-adrenergic receptor adenylyl cyclase pertussis toxin [32P]azidoanilido-GTP (−)-[125I]iodocyanopindolol [32P]nicotinamide adenine dinucleotide dithiothreitol bovine serum albumin Cardiac contractility is controlled by several G protein-coupled receptors (GPCRs),1 such as β1- and β2-adrenergic receptors (β1ARs and β2ARs), that function through stimulatory GTP-binding regulatory proteins (Gαs) and activate adenylyl cyclase (AC). Activation of AC increases the formation of cAMP, which activates cAMP-dependent protein kinase A resulting in the phosphorylation of proteins controlling cardiac excitation-contraction (1Opie L.H. The Heart: Physiology, from Cell to Circulation. Lippincott-Raven, Philadelphia, PA1998: 173-204Google Scholar). An important recent discovery is that β2ARs (but not β1ARs) in both rat (2Xiao R.P., Ji, X. Lakatta E.G. Mol. Pharmacol. 1995; 47: 322-329Crossref PubMed Scopus (198) Google Scholar,3Xiao R.P. Avdonin P. Zhou Y.Y. Cheng H. Akhter S.A. Eschenhagen T. Lefkowitz R.J. Koch W.J. Lakatta E.G. Circ. Res. 1999; 84: 43-52Crossref PubMed Scopus (334) Google Scholar) and human heart (4Kilts J.D. Gerhardt M.A. Richardson M.D. Sreeram G. Mackensen G.B. Grocott H.P. White W.D. Davis R.D. Newman M.F. Reves J.G. Schwinn D.A. Kwatra M.M. Circ. Res. 2000; 87: 705-709Crossref PubMed Scopus (131) Google Scholar) also activate Gαi, a Gα-subunit that inhibits AC (5Lefkowitz R.J. N. Engl. J. Med. 1995; 332: 186-187Crossref PubMed Scopus (27) Google Scholar). We also demonstrated that Gαicouples to several other Gαs-coupled receptors in human heart, including receptors for histamine, glucagon, and serotonin (4Kilts J.D. Gerhardt M.A. Richardson M.D. Sreeram G. Mackensen G.B. Grocott H.P. White W.D. Davis R.D. Newman M.F. Reves J.G. Schwinn D.A. Kwatra M.M. Circ. Res. 2000; 87: 705-709Crossref PubMed Scopus (131) Google Scholar). Coupling of β2AR and other Gαs-coupled receptors to Gαi is relevant to cardiac function because inactivation of Gαi by pertussis toxin (PTX) increases myocyte contractility in rat heart (6Xiao R.P. Tomhave E.D. Wang D.J., Ji, X. Boluyt M.O. Cheng H. Lakatta E.G. Koch W.J. J. Clin. Invest. 1998; 101: 1273-1282Crossref PubMed Scopus (175) Google Scholar) and increases both basal and receptor-mediated AC activity in human heart (4Kilts J.D. Gerhardt M.A. Richardson M.D. Sreeram G. Mackensen G.B. Grocott H.P. White W.D. Davis R.D. Newman M.F. Reves J.G. Schwinn D.A. Kwatra M.M. Circ. Res. 2000; 87: 705-709Crossref PubMed Scopus (131) Google Scholar). In addition to inhibiting AC, the Gαi pathway in heart is involved in anti-apoptotic effects (7Communal C. Singh K. Sawyer D.B. Colucci W.S. Circulation. 1999; 100: 2210-2212Crossref PubMed Scopus (503) Google Scholar, 8Chesley A. Lundberg M.S. Asai T. Xiao R.P. Ohtani S. Lakatta E.G. Crow M.T. Circ. Res. 2000; 87: 1172-1179Crossref PubMed Scopus (343) Google Scholar, 9Zhu W.Z. Zheng M. Koch W.J. Lefkowitz R.J. Kobilka B.K. Xiao R.P. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 1607-1612Crossref PubMed Scopus (376) Google Scholar).The dual coupling of β2AR to both Gαs and Gαi is likely to alter βAR function in diseases in which cardiac Gαi levels are increased, such as congestive heart failure and hypertensive cardiac hypertrophy (10Feldman A.M. Cates A.E. Veazey W.B. Hershberger R.E. Bristow M.R. Baughman K.L. Baumgartner W.A. van Dop C. J. Clin. Invest. 1988; 82: 189-197Crossref PubMed Scopus (458) Google Scholar, 11Bristow M.R. Feldman A.M. Basic Res. Cardiol. 1992; 87: 15-35PubMed Google Scholar, 12Bohm M. Mol. Cell. Biochem. 1995; 147: 147-160Crossref PubMed Scopus (78) Google Scholar, 13Brodde O.E. Michel M.C. Zerkowski H.R. Cardiovasc. Res. 1995; 30: 570-584Crossref PubMed Scopus (109) Google Scholar). Indeed, both congestive heart failure and cardiac hypertrophy are characterized by a reduced responsiveness of βARs. Similarly, a decline in the responsiveness of cardiac βARs due to aging has been demonstrated in both humans (14Vestal R.E. Wood A.J. Shand D.G. Clin. Pharmacol. Ther. 1979; 26: 181-186Crossref PubMed Scopus (490) Google Scholar, 15Kelly J. O'Malley K. Clin. Sci. (Colch.). 1984; 66: 509-515Crossref Scopus (55) Google Scholar, 16White M. Roden R. Minobe W. Khan M.F. Larrabee P. Wollmering M. Port J.D. Anderson F. Campbell D. Feldman A.M. Bristow M.R. Circulation. 1994; 90: 1225-1238Crossref PubMed Scopus (236) Google Scholar, 17Brodde O.E. Zerkowski H.R. Schranz D. Broede-Sitz A. Michel-Reher M. Schafer-Beisenbusch E. Piotrowski J.A. Oelert H. J. Cardiovasc. Pharmacol. 1995; 26: 20-26Crossref PubMed Scopus (83) Google Scholar) and rodents (18Urasawa K. Murakami T. Yasuda H. Jpn. Circ. J. 1991; 55: 676-684Crossref PubMed Scopus (21) Google Scholar, 19Bohm M. Dorner H. Htun P. Lensche H. Platt D. Erdmann E. Am. J. Physiol. 1993; 264: H805-H814PubMed Google Scholar, 20Ferrara N. Bohm M. Zolk O. O'Gara P. Harding S.E. J. Mol. Cell. Cardiol. 1997; 29: 439-448Abstract Full Text PDF PubMed Scopus (26) Google Scholar, 21Roth D.A. White C.D. Podolin D.A. Mazzeo R.S. J. Appl. Physiol. 1998; 84: 177-184Crossref PubMed Scopus (51) Google Scholar). The age-induced decrease in βAR responsiveness is characterized at the molecular level by decreased stimulation of AC and at the whole organ level by a decrease in heart rate, ejection fraction, and cardiac output.There have been conflicting reports about the effect of age on cardiac Gαi levels in both humans and rodents. In one study of human heart, Gαi levels were measured in atrial appendages received from surgical patients, and it was found that Gαi expression increased with age (17Brodde O.E. Zerkowski H.R. Schranz D. Broede-Sitz A. Michel-Reher M. Schafer-Beisenbusch E. Piotrowski J.A. Oelert H. J. Cardiovasc. Pharmacol. 1995; 26: 20-26Crossref PubMed Scopus (83) Google Scholar). Another study examined Gαi expression in human ventricles from hearts that were not suitable for transplant and found no change in Gαi with age (16White M. Roden R. Minobe W. Khan M.F. Larrabee P. Wollmering M. Port J.D. Anderson F. Campbell D. Feldman A.M. Bristow M.R. Circulation. 1994; 90: 1225-1238Crossref PubMed Scopus (236) Google Scholar). Similar studies in rat heart have yielded inconsistent results even when the same strain of rat was used. In Fisher 344 rats, Roth et al. (21Roth D.A. White C.D. Podolin D.A. Mazzeo R.S. J. Appl. Physiol. 1998; 84: 177-184Crossref PubMed Scopus (51) Google Scholar) reported an age-associated increase in cardiac Gαi, which is reduced by chronic dynamic exercise. Johnson et al. (22Johnson M.D. Zhou Y. Friedman E. Roberts J. J. Gerontol. A. Biol. Sci. Med. Sci. 1995; 50A: B14-B19Crossref PubMed Scopus (32) Google Scholar) found an increase in Gαi mRNA but no change in Gαi protein. Two other reports found no increase in cardiac Gαi protein (23Shu Y. Scarpace P.J. J. Cardiovasc. Pharmacol. 1994; 23: 188-193Crossref PubMed Google Scholar, 24Chin J.H. Hiremath A.N. Hoffman B.B. Mech. Ageing. Dev. 1996; 86: 11-26Crossref PubMed Scopus (28) Google Scholar). In Sprague-Dawley rats, Bohm et al. (19Bohm M. Dorner H. Htun P. Lensche H. Platt D. Erdmann E. Am. J. Physiol. 1993; 264: H805-H814PubMed Google Scholar) found that age increases cardiac Gαi, and the increase in Gαi is reduced by exercise. In Wistar rats, Bazan et al. (25Bazan A. van de Velde E. Fraeyman N. Biochem. Pharmacol. 1994; 48: 479-486Crossref PubMed Scopus (28) Google Scholar) reported an increase in cardiac Gαi with age, but Xiao et al. (6Xiao R.P. Tomhave E.D. Wang D.J., Ji, X. Boluyt M.O. Cheng H. Lakatta E.G. Koch W.J. J. Clin. Invest. 1998; 101: 1273-1282Crossref PubMed Scopus (175) Google Scholar) and Miyamoto et al. (26Miyamoto A. Kawana S. Kimura H. Ohshika H. Eur. J. Pharmacol. 1994; 266: 147-154Crossref PubMed Scopus (38) Google Scholar) found no change. Some of the reported differences on the effect of age may be attributable to experimental design. For example, the finding of Chin et al.(24Chin J.H. Hiremath A.N. Hoffman B.B. Mech. Ageing. Dev. 1996; 86: 11-26Crossref PubMed Scopus (28) Google Scholar) that age does not increase cardiac Gαi in Fisher 344 rats may be explained by the fact that these investigators used 16-month-old rats for their old age group versus24-month-old rats used by others. Moreover, most studies examined Gαi expression by immunoblotting only, and different Gαi antibodies were used. Nevertheless, the available evidence favors an increase in Gαi with age, as indicated by the recent review of Roka et al. (27Roka F. Freissmuth M. Nanoff C. Exp. Gerontol. 2000; 35: 133-143Crossref PubMed Scopus (13) Google Scholar). However, two recent reviews by Lakatta (28Lakatta E.G. J. Am. Geriatr. Soc. 1999; 47: 613-625Crossref PubMed Scopus (124) Google Scholar, 29Lakatta E.G. Am. J. Geriatr. Cardiol. 2000; 9: 251-262Crossref PubMed Scopus (12) Google Scholar) on global changes in cardiovascular aging state that Gαi in heart does not increase with age. We believe that this conclusion is premature.The importance of Gαi in cardiac function underscores the need to establish whether or not cardiac Gαi is affected with age. Therefore, we undertook a detailed study on the effect of age on Gαi expression in rat ventricular membranes. We used Fisher 344 rats because these rats have been the most widely used rat strain for aging studies (30Weindruch R. Masoro E.J. J. Gerontol. 1991; 46: B87-B88Crossref PubMed Google Scholar), and age-induced changes in cardiac structure have been characterized (31Anversa P. Palackal T. Sonnenblick E.H. Olivetti G. Meggs L.G. Capasso J.M. Circ. Res. 1990; 67: 871-885Crossref PubMed Scopus (346) Google Scholar). Expression of the predominant cardiac subtypes of Gαi, as well as of Gαs, Gαo, and the major subtypes of Gβ, was assessed by immunoblotting. Levels of PTX-sensitive Gαi/Gαo proteins were also examined by radiolabeling through PTX-catalyzed ADP-ribosylation. In addition, Gαi2 activity was assessed using photoaffinity labeling with [32P]azidoanilido-GTP (AA-[32P]GTP). We show age-dependent increases in both Gαi2expression levels and activation of Gαi2 by β2AR and other G protein-coupled receptors in heart. The age-induced increase in Gαi2 has the functional effect of suppressing AC activity, which is restored by disrupting receptor-Gαi coupling with PTX.DISCUSSIONThe main finding of the present study is that Gαi2expression in rat left ventricle increases with age. The increase in Gαi2 expression is demonstrated using several biochemical techniques including immunoblotting, ADP-ribosylation, and photoaffinity labeling with AA-[32P]GTP. The increase in Gαi2 results in enhanced coupling to Gαs-coupled receptors such as β2ARs and glucagon receptors, as well as to Gαi-coupled muscarinic receptors. Thus, the net effect of the increase in Gαi2expression with age is an increase in Gαi2 signaling. This results in reductions in both basal and receptor-mediated AC activities in aged heart, both of which are restored by disabling of Gαi with PTX.The present study examined the effect of age on cardiac Gαi, an important issue about which conflicting data exist in the literature. Determination of the effects of age on Gαi has become increasingly important in light of the recent demonstrations that many cardiac Gαs-coupled receptors, including β2AR, also couple to Gαi (2Xiao R.P., Ji, X. Lakatta E.G. Mol. Pharmacol. 1995; 47: 322-329Crossref PubMed Scopus (198) Google Scholar, 3Xiao R.P. Avdonin P. Zhou Y.Y. Cheng H. Akhter S.A. Eschenhagen T. Lefkowitz R.J. Koch W.J. Lakatta E.G. Circ. Res. 1999; 84: 43-52Crossref PubMed Scopus (334) Google Scholar, 4Kilts J.D. Gerhardt M.A. Richardson M.D. Sreeram G. Mackensen G.B. Grocott H.P. White W.D. Davis R.D. Newman M.F. Reves J.G. Schwinn D.A. Kwatra M.M. Circ. Res. 2000; 87: 705-709Crossref PubMed Scopus (131) Google Scholar). The data in the present study clearly indicate an increased level of Gαi2 in old Fisher 344 rats, and importantly, also demonstrate an elevation in the receptor-stimulated activation of Gαi2. Prior studies in rats had not provided a consensus as to the effects of age on cardiac Gαi. There have been reports of increased Gαi expression in Fisher 344 (21Roth D.A. White C.D. Podolin D.A. Mazzeo R.S. J. Appl. Physiol. 1998; 84: 177-184Crossref PubMed Scopus (51) Google Scholar), Sprague-Dawley (19Bohm M. Dorner H. Htun P. Lensche H. Platt D. Erdmann E. Am. J. Physiol. 1993; 264: H805-H814PubMed Google Scholar) and Wistar rats (25Bazan A. van de Velde E. Fraeyman N. Biochem. Pharmacol. 1994; 48: 479-486Crossref PubMed Scopus (28) Google Scholar), as well as an increase in Fisher 344 Gαi mRNA (22Johnson M.D. Zhou Y. Friedman E. Roberts J. J. Gerontol. A. Biol. Sci. Med. Sci. 1995; 50A: B14-B19Crossref PubMed Scopus (32) Google Scholar). However, there also have been reports of no change in Gαi expression in Fisher 344 (22Johnson M.D. Zhou Y. Friedman E. Roberts J. J. Gerontol. A. Biol. Sci. Med. Sci. 1995; 50A: B14-B19Crossref PubMed Scopus (32) Google Scholar, 23Shu Y. Scarpace P.J. J. Cardiovasc. Pharmacol. 1994; 23: 188-193Crossref PubMed Google Scholar) and Wistar rats (6Xiao R.P. Tomhave E.D. Wang D.J., Ji, X. Boluyt M.O. Cheng H. Lakatta E.G. Koch W.J. J. Clin. Invest. 1998; 101: 1273-1282Crossref PubMed Scopus (175) Google Scholar, 26Miyamoto A. Kawana S. Kimura H. Ohshika H. Eur. J. Pharmacol. 1994; 266: 147-154Crossref PubMed Scopus (38) Google Scholar). These differences make it necessary to examine Gαi by multiple biochemical approaches. Our data indicating Gαi2 increases in immunoblotting, ADP-ribosylation and photoaffinity labeling lead us to conclude that there is a significant age-dependent elevation in Fisher 344 cardiac Gαi2. The increase in Gαi2 in aged hearts is likely not due to hypertrophy because in Fisher 344 rats hypertrophy is seen at senescence, which occurs at 27–30 months of age (31Anversa P. Palackal T. Sonnenblick E.H. Olivetti G. Meggs L.G. Capasso J.M. Circ. Res. 1990; 67: 871-885Crossref PubMed Scopus (346) Google Scholar).In agreement with previous reports in both human (15Kelly J. O'Malley K. Clin. Sci. (Colch.). 1984; 66: 509-515Crossref Scopus (55) Google Scholar, 16White M. Roden R. Minobe W. Khan M.F. Larrabee P. Wollmering M. Port J.D. Anderson F. Campbell D. Feldman A.M. Bristow M.R. Circulation. 1994; 90: 1225-1238Crossref PubMed Scopus (236) Google Scholar, 17Brodde O.E. Zerkowski H.R. Schranz D. Broede-Sitz A. Michel-Reher M. Schafer-Beisenbusch E. Piotrowski J.A. Oelert H. J. Cardiovasc. Pharmacol. 1995; 26: 20-26Crossref PubMed Scopus (83) Google Scholar) and rat heart (21Roth D.A. White C.D. Podolin D.A. Mazzeo R.S. J. Appl. Physiol. 1998; 84: 177-184Crossref PubMed Scopus (51) Google Scholar, 23Shu Y. Scarpace P.J. J. Cardiovasc. Pharmacol. 1994; 23: 188-193Crossref PubMed Google Scholar, 48O'Connor S.W. Scarpace P.J. Abrass I.B. Mech. Ageing Dev. 1983; 21: 357-363Crossref PubMed Scopus (55) Google Scholar, 49Fan T.H. Banerjee S.P. Gerontology. 1985; 31: 373-380Crossref PubMed Scopus (25) Google Scholar, 50Scarpace P.J. Mech. Ageing Dev. 1990; 52: 169-178Crossref PubMed Scopus (42) Google Scholar, 51Scarpace P.J. Shu Y. Tumer N. J. Appl. Physiol. 1994; 77: 737-741Crossref PubMed Scopus (27) Google Scholar), we also demonstrate decreases in AC activity in old heart. To explain this phenomenon, some studies have implicated changes at the level of AC. There has been a report of a decrease in the number of forskolin binding sites in old rats (23Shu Y. Scarpace P.J. J. Cardiovasc. Pharmacol. 1994; 23: 188-193Crossref PubMed Google Scholar), indicating a lower amount of AC in old tissue, though there have been no reports on AC mRNA levels in Fisher 344 rats. Although decreases in AC activity with age could be due to decreased amounts of AC or its targets, the fact that PTX treatment restores β2AR- and glucagon receptor-stimulated AC signals in older hearts to the levels in younger hearts indicates that PTX-sensitive proteins are responsible for the decreased receptor-stimulated enzyme activity. PTX treatment in both guinea pig heart and rat bladder results in similar reversals of age-induced decreases in AC (20Ferrara N. Bohm M. Zolk O. O'Gara P. Harding S.E. J. Mol. Cell. Cardiol. 1997; 29: 439-448Abstract Full Text PDF PubMed Scopus (26) Google Scholar, 52Derweesh I.H. Wheeler M.A. Weiss R.M. J. Pharmacol. Exp. Ther. 2000; 294: 969-974PubMed Google Scholar). We conclude that elevated Gαi is the main cause of reduced AC activity in aged rat left ventricles.Apparently, an increase in cardiac Gαi in aged rat heart does not affect βAR-mediated contractility. Although coupling of β1ARs to stimulation of AC and contractility through Gαs is widely accepted, questions remain as to whether effects on contractility through β2AR involve cAMP. In humans, stimulation of contractility via β2ARs has been reported to occur through a cAMP-dependent mechanism that results in protein kinase A-catalyzed phosphorylation of phospholamban, troponin I, and C-protein, as well as enhancement of both inotropy and lusitropy, in both non-failing (53Kaumann A.J. Sanders L. Lynham J.A. Bartel S. Kuschel M. Karczewski P. Krause E.G. Mol. Cell. Biochem. 1996; 163/164: 113-123Crossref Scopus (51) Google Scholar) and failing human heart (54Kaumann A. Bartel S. Molenaar P. Sanders L. Burrell K. Vetter D. Hempel P. Karczewski P. Krause E.G. Circulation. 1999; 99: 65-72Crossref PubMed Scopus (111) Google Scholar), as well as in non-failing myocardium from infants with Fallot tetralogy (55Molenaar P. Bartel S. Cochrane A. Vetter D. Jalali H. Pohlner P. Burrell K. Karczewski P. Krause E.G. Kaumann A. Circulation. 2000; 102: 1814-1821Crossref PubMed Scopus (60) Google Scholar). Therefore, one would expect that in humans, an increase in the coupling of β2AR to Gαi would lower contractility. In contrast, cAMP-independent pathways control β2AR-mediated contractility in rat (2Xiao R.P., Ji, X. Lakatta E.G. Mol. Pharmacol. 1995; 47: 322-329Crossref PubMed Scopus (198) Google Scholar, 56Xiao R.P. Lakatta E.G. Circ. Res. 1993; 73: 286-300Crossref PubMed Scopus (209) Google Scholar, 57Xiao R.P. Hohl C. Altschuld R. Jones L. Livingston B. Ziman B. Tantini B. Lakatta E.G. J. Biol. Chem. 1994; 269: 19151-19156Abstract Full Text PDF PubMed Google Scholar, 58Jiang T. Steinberg S.F. Am. J. Physiol. 1997; 273: H1044-H1047Crossref PubMed Google Scholar), cat (59Lemoine H. Kaumann A.J. Naunyn-Schmiedeberg's Arch. Pharmacol. 1991; 344: 56-69Crossref PubMed Scopus (55) Google Scholar), sheep (60Borea P.A. Amerini S. Masini I. Cerbai E. Ledda F. Mantelli L. Varani K. Mugelli A. J. Mol. Cell. Cardiol. 1992; 24: 753-763Abstract Full Text PDF PubMed Scopus (31) Google Scholar), and dog (61Altschuld R.A. Starling R.C. Hamlin R.L. Billman G.E. Hensley J. Castillo L. Fertel R.H. Hohl C.M. Robitaille P.M. Jones L.R. Xiao R.P. Lakatta E.G. Circulation. 1995; 92: 1612-1618Crossref PubMed Scopus (124) Google Scholar). Thus, in these species, an age-induced increase in Gαi would not decrease β2AR-mediated contractility. Consistent with this notion is the finding of Jain et al. (62Jain M. Lim C.C. Nagata K. Davis V.M. Milstone D.S. Liao R. Mortensen R.M. Am. J. Physiol. Heart Circ. Physiol. 2001; 280: H569-H575Crossref PubMed Google Scholar) who found no difference in basal contractile and relaxation function in mice lacking either Gαi2 or Gαi3.An important functional consequence of an age-induced increase in the coupling of cardiac β2AR to Gαi2 may be increased inhibition of apoptosis. It was shown recently that norepinephrine, acting through a Gαs pathway, increases cardiac apoptosis (63Communal C. Singh K. Pimentel D.R. Colucci W.S. Circulation. 1998; 98: 1329-1334Crossref PubMed Scopus (592) Google Scholar, 64Gu C., Ma, Y.C. Benjamin J. Littman D. Chao M.V. Huang X.Y. J. Biol. Chem. 2000; 275: 20726-20733Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). More recent data indicate that β1ARs cause apoptosis, whereas β2ARs acting through a Gαi pathway oppose apoptosis (7Communal C. Singh K. Sawyer D.B. Colucci W.S. Circulation. 1999; 100: 2210-2212Crossref PubMed Scopus (503) Google Scholar, 8Chesley A. Lundberg M.S. Asai T. Xiao R.P. Ohtani S. Lakatta E.G. Crow M.T. Circ. Res. 2000; 87: 1172-1179Crossref PubMed Scopus (343) Google Scholar, 9Zhu W.Z. Zheng M. Koch W.J. Lefkowitz R.J. Kobilka B.K. Xiao R.P. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 1607-1612Crossref PubMed Scopus (376) Google Scholar). In adult rat ventricular myocytes, stimulation of a PTX-sensitive Gαi-coupled pathway by β2AR inhibits the number of apoptotic cells as measured by flow cytometry (7Communal C. Singh K. Sawyer D.B. Colucci W.S. Circulation. 1999; 100: 2210-2212Crossref PubMed Scopus (503) Google Scholar). Using a neonatal rat myocyte model, it was shown that β2AR/Gαi-mediated protection from apoptosis occurs through phosphatidylinositol 3-kinase (PI 3-kinase) and Akt/protein kinase B pathways (8Chesley A. Lundberg M.S. Asai T. Xiao R.P. Ohtani S. Lakatta E.G. Crow M.T. Circ. Res. 2000; 87: 1172-1179Crossref PubMed Scopus (343) Google Scholar). The β2AR/Gαi/PI 3-kinase signaling mechanism also has been shown to mediate the stimulation of NO production (65Wang Y.G. Dedkova E.N. Steinberg S.F. Blatter L.A. Lipsius S.L. J. Gen. Physiol. 2002; 119: 69-82Crossref PubMed Scopus (22) Google Scholar), a key mechanism in the cardioprotection conferred by ischemic preconditioning (66Ping P. Takano H. Zhang J. Tang X.L. Qiu Y., Li, R.C. Banerjee S. Dawn B. Balafonova Z. Bolli R. Circ. Res. 1999; 84: 587-604Crossref PubMed Scopus (230) Google Scholar). Finally, β2AR- mediated protection from apoptosis recently has been reported to occur through a Gαi-dependent stimulation of p38 kinase (67Communal C. Colucci W.S. Singh K. J. Biol. Chem. 2000; 275: 19395-19400Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar), though another study reports that β2AR activates p38 kinase through a protein kinase A-dependent pathway that does not involve Gαi (68Zheng M. 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An important recent discovery is that β2ARs (but not β1ARs) in both rat (2Xiao R.P., Ji, X. Lakatta E.G. Mol. Pharmacol. 1995; 47: 322-329Crossref PubMed Scopus (198) Google Scholar,3Xiao R.P. Avdonin P. Zhou Y.Y. Cheng H. Akhter S.A. Eschenhagen T. Lefkowitz R.J. Koch W.J. Lakatta E.G. Circ. Res. 1999; 84: 43-52Crossref PubMed Scopus (334) Google Scholar) and human heart (4Kilts J.D. Gerhardt M.A. Richardson M.D. Sreeram G. Mackensen G.B. Grocott H.P. White W.D. Davis R.D. Newman M.F. Reves J.G. Schwinn D.A. Kwatra M.M. Circ. Res. 2000; 87: 705-709Crossref PubMed Scopus (131) Google Scholar) also activate Gαi, a Gα-subunit that inhibits AC (5Lefkowitz R.J. N. Engl. J. Med. 1995; 332: 186-187Crossref PubMed Scopus (27) Google Scholar). We also demonstrated that Gαicouples to several other Gαs-coupled receptors in human heart, including receptors for histamine, glucagon, and serotonin (4Kilts J.D. Gerhardt M.A. Richardson M.D. Sreeram G. Mackensen G.B. Grocott H.P. White W.D. Davis R.D. Newman M.F. Reves J.G. Schwinn D.A. Kwatra M.M. Circ. Res. 2000; 87: 705-709Crossref PubMed Scopus (131) Google Scholar). Coupling of β2AR and other Gαs-coupled receptors to Gαi is relevant to cardiac function because inactivation of Gαi by pertussis toxin (PTX) increases myocyte contractility in rat heart (6Xiao R.P. Tomhave E.D. Wang D.J., Ji, X. Boluyt M.O. Cheng H. Lakatta E.G. Koch W.J. J. Clin. Invest. 1998; 101: 1273-1282Crossref PubMed Scopus (175) Google Scholar) and increases both basal and receptor-mediated AC activity in human heart (4Kilts J.D. Gerhardt M.A. Richardson M.D. Sreeram G. Mackensen G.B. Grocott H.P. White W.D. Davis R.D. Newman M.F. Reves J.G. Schwinn D.A. Kwatra M.M. Circ. Res. 2000; 87: 705-709Crossref PubMed Scopus (131) Google Scholar). In addition to inhibiting AC, the Gαi pathway in heart is involved in anti-apoptotic effects (7Communal C. Singh K. Sawyer D.B. Colucci W.S. Circulation. 1999; 100: 2210-2212Crossref PubMed Scopus (503) Google Scholar, 8Chesley A. Lundberg M.S. Asai T. Xiao R.P. Ohtani S. Lakatta E.G. Crow M.T. Circ. Res. 2000; 87: 1172-1179Crossref PubMed Scopus (343) Google Scholar, 9Zhu" @default.
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