Adrenergic receptors in individual ventricular myocytes: the beta-1 and alpha-1B are in all cells, the alpha-1A is in a subpopulation, and the beta-2 and beta-3 are mostly absent

Circulation Research

Volumn 120, Issue 7, 2017, Pages 1103-1115

  Myagmar, Bat Erdene ^a,b   Flynn, James M ^c,h   Cowley, Patrick M ^a,b   Swigart, Philip M ^a   Montgomery, Megan D ^a,b,d   Thai, Kevin ^a   Nair, Divya ^a,g   Gupta, Rumita ^a   Deng, David X ^a,b,e   Hosoda, Chihiro ^a,b,f   Melov, Simon ^c   Baker, Anthony J ^a,b   Simpson, Paul C ^a,b  

^a VETERANS AFFAIRS MEDICAL CENTER   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c BUCK INSTITUTE FOR RESEARCH ON AGING   (United States)

^d Amarin Pharma Inc   (United States)

^e Ardent BioMed Inc   (United States)

^f Takagi Hospital   (Japan)

^g WEIZMANN INSTITUTE OF SCIENCE   (Israel)

^h Biorad Labs   (United States)

Author keywords

adrenergic agents; mice, knockout; myocytes, cardiac; receptors, adrenergic; receptors, adrenergic, alpha 1; receptors, adrenergic, beta

Indexed keywords

3 ISOPROPYLAMINO 1 (7 METHYL 4 INDANYLOXY) 2 BUTANOL; 4 [2 [[2 (3 CHLOROPHENYL) 2 HYDROXYETHYL]AMINO]PROPYL]PHENOXYACETIC ACID; ALPHA 1A ADRENERGIC RECEPTOR; BETA 1 ADRENERGIC RECEPTOR; BETA 3 ADRENERGIC RECEPTOR; ISOETARINE; MESSENGER RNA; MITOGEN ACTIVATED PROTEIN KINASE; N [5 (4,5 DIHYDRO 1H IMIDAZOL 2 YL) 5,6,7,8 TETRAHYDRO 2 HYDROXY 1 NAPHTHYL]METHANESULFONAMIDE; PHOSPHOLAMBAN; ROLIPRAM; ALPHA ADRENERGIC RECEPTOR; BETA ADRENERGIC RECEPTOR;

ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; CARDIAC MUSCLE CELL; CELL SUBPOPULATION; CONTROLLED STUDY; ENZYME ACTIVITY; ENZYME PHOSPHORYLATION; HEART PROTECTION; IMMUNOCYTOCHEMISTRY; INOTROPISM; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; RAT; SIGNAL TRANSDUCTION; ANIMAL; C57BL MOUSE; CELL CULTURE; CYTOLOGY; GENETICS; HEART VENTRICLE; METABOLISM; SINGLE CELL ANALYSIS;

ANIMALS; CELLS, CULTURED; HEART VENTRICLES; MALE; MICE; MICE, INBRED C57BL; MYOCYTES, CARDIAC; RECEPTORS, ADRENERGIC, ALPHA; RECEPTORS, ADRENERGIC, BETA; RNA, MESSENGER; SINGLE-CELL ANALYSIS;

EID: 85013754278     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.117.310520     Document Type: Article

References (72)

1. Lymperopoulos A, Rengo G, Koch WJ, Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ Res 2013 113 739 753. doi: 10.1161/CIRCRESAHA.113.300308.
2. Woo AY, Song Y, Xiao RP, Zhu W, Biased β2-adrenoceptor signalling in heart failure: pathophysiology and drug discovery. Br J Pharmacol 2015 172 5444 5456. doi: 10.1111/bph.12965.
3. O'Connell TD, Jensen BC, Baker AJ, Simpson PC, Cardiac alpha1-adrenergic receptors: novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. Pharmacol Rev 2014 66 308 333. doi: 10.1124/pr.112.007203.
4. Simpson PC, A new pathway for sympathetic cardioprotection in heart failure. Circ Res 2015 117 592 595. doi: 10.1161/CIRCRESAHA.115.307246.
5. Baker AJ, Adrenergic signaling in heart failure: a balance of toxic and protective effects. Pflugers Arch 2014 466 1139 1150. doi: 10.1007/s00424-014-1491-5.
6. Rokosh DG, Simpson PC, Knockout of the alpha 1A/C-adrenergic receptor subtype: the alpha 1A/C is expressed in resistance arteries and is required to maintain arterial blood pressure. Proc Natl Acad Sci U S A 2002 99 9474 9479. doi: 10.1073/pnas.132552699.
7. Flynn JM, Santana LF, Melov S, Single cell transcriptional profiling of adult mouse cardiomyocytes. J Vis Exp 2011 e3302
8. Jensen BC, Swigart PM, Simpson PC, Ten commercial antibodies for alpha-1-adrenergic receptor subtypes are nonspecific. Naunyn Schmiedebergs Arch Pharmacol 2009 379 409 412. doi: 10.1007/s00210-008-0368-6.
9. Huang Y, Wright CD, Merkwan CL, Baye NL, Liang Q, Simpson PC, O'Connell TD, An alpha1A-adrenergic-extracellular signal-regulated kinase survival signaling pathway in cardiac myocytes. Circulation 2007 115 763 772. doi: 10.1161/CIRCULATIONAHA.106.664862.
10. Knepper SM, Buckner SA, Brune ME, DeBernardis JF, Meyer MD, Hancock AA, A-61603, a potent alpha 1-adrenergic receptor agonist, selective for the alpha 1A receptor subtype. J Pharmacol Exp Ther 1995 274 97 103
11. McCloskey DT, Rokosh DG, O'Connell TD, Keung EC, Simpson PC, Baker AJ, Alpha(1)-adrenoceptor subtypes mediate negative inotropy in myocardium from alpha(1A/C)-knockout and wild type mice. J Mol Cell Cardiol 2002 34 1007 1017
12. Chu C, Thai K, Park KW, Wang P, Makwana O, Lovett DH, Simpson PC, Baker AJ, Intraventricular and interventricular cellular heterogeneity of inotropic responses to α(1)-adrenergic stimulation. Am J Physiol Heart Circ Physiol 2013 304 H946 H953. doi: 10.1152/ajpheart.00822.2012.
13. O'Connell TD, Ishizaka S, Nakamura A, Swigart PM, Rodrigo MC, Simpson GL, Cotecchia S, Rokosh DG, Grossman W, Foster E, Simpson PC, The alpha(1A/C)- and alpha(1B)-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse. J Clin Invest 2003 111 1783 1791. doi: 10.1172/JCI16100.
14. Rybin VO, Guo J, Gertsberg Z, Elouardighi H, Steinberg SF, Protein kinase Cepsilon (PKCepsilon) and Src control PKCdelta activation loop phosphorylation in cardiomyocytes. J Biol Chem 2007 282 23631 23638. doi: 10.1074/jbc.M701676200.
15. Pinto AR, Ilinykh A, Ivey MJ, Kuwabara JT, D'Antoni ML, Debuque R, Chandran A, Wang L, Arora K, Rosenthal NA, Tallquist MD, Revisiting Cardiac Cellular Composition. Circ Res 2016 118 400 409. doi: 10.1161/CIRCRESAHA.115.307778.
16. Zhou P, Pu WT, Recounting cardiac cellular composition. Circ Res 2016 118 368 370. doi: 10.1161/CIRCRESAHA.116.308139.
17. Meszaros JG, Gonzalez AM, Endo-Mochizuki Y, Villegas S, Villarreal F, Brunton LL, Identification of G protein-coupled signaling pathways in cardiac fibroblasts: cross talk between G(q) and G(s). Am J Physiol Cell Physiol 2000 278 C154 C162
18. Gustafsson AB, Brunton LL, beta-adrenergic stimulation of rat cardiac fibroblasts enhances induction of nitric-oxide synthase by interleukin-1beta via message stabilization. Mol Pharmacol 2000 58 1470 1478
19. Leicht M, Greipel N, Zimmer H, Comitogenic effect of catecholamines on rat cardiac fibroblasts in culture. Cardiovasc Res 2000 48 274 284
20. Turner NA, Porter KE, Smith WH, White HL, Ball SG, Balmforth AJ, Chronic beta2-adrenergic receptor stimulation increases proliferation of human cardiac fibroblasts via an autocrine mechanism. Cardiovasc Res 2003 57 784 792
21. Michel MC, Wieland T, Tsujimoto G, How reliable are G-protein-coupled receptor antibodies? Naunyn Schmiedebergs Arch Pharmacol 2009 379 385 388. doi: 10.1007/s00210-009-0395-y.
22. Kuschel M, Zhou YY, Cheng H, Zhang SJ, Chen Y, Lakatta EG, Xiao RP, G(i) protein-mediated functional compartmentalization of cardiac beta(2)-adrenergic signaling. J Biol Chem 1999 274 22048 22052
23. Soto D, De Arcangelis V, Zhang J, Xiang Y, Dynamic protein kinase a activities induced by beta-adrenoceptors dictate signaling propagation for substrate phosphorylation and myocyte contraction. Circ Res 2009 104 770 779. doi: 10.1161/CIRCRESAHA.108.187880.
24. Liu R, Ramani B, Soto D, De Arcangelis V, Xiang Y, Agonist dose-dependent phosphorylation by protein kinase A and G protein-coupled receptor kinase regulates beta2 adrenoceptor coupling to G(i) proteins in cardiomyocytes. J Biol Chem 2009 284 32279 32287
25. Bartel S, Krause EG, Wallukat G, Karczewski P, New insights into beta2-adrenoceptor signaling in the adult rat heart. Cardiovasc Res 2003 57 694 703
26. Xiang Y, Naro F, Zoudilova M, Jin SL, Conti M, Kobilka B, Phosphodiesterase 4D is required for beta2 adrenoceptor subtype-specific signaling in cardiac myocytes. Proc Natl Acad Sci U S A 2005 102 909 914. doi: 10.1073/pnas.0405263102.
27. Balligand JL, Cardiac salvage by tweaking with beta-3-adrenergic receptors. Cardiovasc Res 2016 111 128 133. doi: 10.1093/cvr/cvw056.
28. Hamdani N, van der Velden J, Lack of specificity of antibodies directed against human beta-adrenergic receptors. Naunyn Schmiedebergs Arch Pharmacol 2009 379 403 407. doi: 10.1007/s00210-009-0392-1.
29. Pradidarcheep W, Stallen J, Labruyère WT, Dabhoiwala NF, Michel MC, Lamers WH, Lack of specificity of commercially available antisera against muscarinergic and adrenergic receptors. Naunyn Schmiedebergs Arch Pharmacol 2009 379 397 402. doi: 10.1007/s00210-009-0393-0.
30. Böhmer T, Pfeiffer N, Gericke A, Three commercial antibodies against α1-adrenergic receptor subtypes lack specificity in paraffin-embedded sections of murine tissues. Naunyn Schmiedebergs Arch Pharmacol 2014 387 703 706. doi: 10.1007/s00210-014-0992-2.
31. Rybin VO, Pak E, Alcott S, Steinberg SF, Developmental changes in beta2-adrenergic receptor signaling in ventricular myocytes: the role of Gi proteins and caveolae microdomains. Mol Pharmacol 2003 63 1338 1348. doi: 10.1124/mol.63.6.1338.
32. Xiao RP, Lakatta EG, Beta 1-adrenoceptor stimulation and beta 2-adrenoceptor stimulation differ in their effects on contraction, cytosolic Ca2+, and Ca2+ current in single rat ventricular cells. Circ Res 1993 73 286 300
33. Kuznetsov V, Pak E, Robinson RB, Steinberg SF, Beta 2-adrenergic receptor actions in neonatal and adult rat ventricular myocytes. Circ Res 1995 76 40 52
34. Altschuld RA, Starling RC, Hamlin RL, Billman GE, Hensley J, Castillo L, Fertel RH, Hohl CM, Robitaille PM, Jones LR, Response of failing canine and human heart cells to beta 2-adrenergic stimulation. Circulation 1995 92 1612 1618
35. Jiang T, Steinberg SF, Beta 2-adrenergic receptors enhance contractility by stimulating HCO3(-)-dependent intracellular alkalinization. Am J Physiol 1997 273 H1044 H1047
36. Xiao RP, Avdonin P, Zhou YY, Cheng H, Akhter SA, Eschenhagen T, Lefkowitz RJ, Koch WJ, Lakatta EG, Coupling of beta2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes. Circ Res 1999 84 43 52
37. Communal C, Singh K, Sawyer DB, Colucci WS, Opposing effects of beta(1)- and beta(2)-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis toxin-sensitive G protein. Circulation 1999 100 2210 2212
38. Sabri A, Pak E, Alcott SA, Wilson BA, Steinberg SF, Coupling function of endogenous alpha(1)- and beta-adrenergic receptors in mouse cardiomyocytes. Circ Res 2000 86 1047 1053
39. Chesley A, Lundberg MS, Asai T, Xiao RP, Ohtani S, Lakatta EG, Crow MT, The beta(2)-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through G(i)-dependent coupling to phosphatidylinositol 3'-kinase. Circ Res 2000 87 1172 1179
40. Desantiago J, Ai X, Islam M, Acuna G, Ziolo MT, Bers DM, Pogwizd SM, Arrhythmogenic effects of beta2-adrenergic stimulation in the failing heart are attributable to enhanced sarcoplasmic reticulum Ca load. Circ Res 2008 102 1389 1397. doi: 10.1161/CIRCRESAHA.107.169011.
41. Nikolaev VO, Moshkov A, Lyon AR, Miragoli M, Novak P, Paur H, Lohse MJ, Korchev YE, Harding SE, Gorelik J, Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science 2010 327 1653 1657. doi: 10.1126/science.1185988.
42. 2-adrenergic receptor-mediated G(i) signaling. J Mol Cell Cardiol 2011 50 1000 1007. doi: 10.1016/j.yjmcc.2011.01.015.
43. Macdougall DA, Agarwal SR, Stopford EA, Chu H, Collins JA, Longster AL, Colyer J, Harvey RD, Calaghan S, Caveolae compartmentalise β2-adrenoceptor signals by curtailing cAMP production and maintaining phosphatase activity in the sarcoplasmic reticulum of the adult ventricular myocyte. J Mol Cell Cardiol 2012 52 388 400. doi: 10.1016/j.yjmcc.2011.06.014.
44. Sysa-Shah P, Tocchetti CG, Gupta M, Bidirectional cross-regulation between ErbB2 and β-adrenergic signalling pathways. Cardiovasc Res 2016 109 358 373. doi: 10.1093/cvr/cvv274.
45. Baker JG, The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. Br J Pharmacol 2010 160 1048 1061. doi: 10.1111/j.1476-5381.2010.00754.x.
46. Smith C, Teitler M, Beta-blocker selectivity at cloned human beta 1- and beta 2-adrenergic receptors. Cardiovasc Drugs Ther 1999 13 123 126
47. Baker JG, The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors. Br J Pharmacol 2005 144 317 322. doi: 10.1038/sj.bjp.0706048.
48. Moniotte S, Kobzik L, Feron O, Trochu JN, Gauthier C, Balligand JL, Upregulation of beta(3)-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium. Circulation 2001 103 1649 1655
49. Cheng HJ, Zhang ZS, Onishi K, Ukai T, Sane DC, Cheng CP, Upregulation of functional beta(3)-adrenergic receptor in the failing canine myocardium. Circ Res 2001 89 599 606
50. Moniotte S, Belge C, Sekkali B, Massion PB, Rozec B, Dessy C, Balligand JL, Sepsis is associated with an upregulation of functional beta3 adrenoceptors in the myocardium. Eur J Heart Fail 2007 9 1163 1171. doi: 10.1016/j.ejheart.2007.10.006.
51. Vrydag W, Michel MC, Tools to study beta3-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol 2007 374 385 398. doi: 10.1007/s00210-006-0127-5.
52. Cernecka H, Sand C, Michel MC, The odd sibling: features of β3-adrenoceptor pharmacology. Mol Pharmacol 2014 86 479 484. doi: 10.1124/mol.114.092817.
53. Buxton IL, Brunton LL, Direct analysis of beta-adrenergic receptor subtypes on intact adult ventricular myocytes of the rat. Circ Res 1985 56 126 132
54. Zhu WZ, Chakir K, Zhang S, Yang D, Lavoie C, Bouvier M, Hébert TE, Lakatta EG, Cheng H, Xiao RP, Heterodimerization of beta1- and beta2-adrenergic receptor subtypes optimizes beta-adrenergic modulation of cardiac contractility. Circ Res 2005 97 244 251. doi: 10.1161/01.RES.0000176764.38934.86.
55. Zhou YY, Yang D, Zhu WZ, Zhang SJ, Wang DJ, Rohrer DK, Devic E, Kobilka BK, Lakatta EG, Cheng H, Xiao RP, Spontaneous activation of beta(2)- but not beta(1)-adrenoceptors expressed in cardiac myocytes from beta(1)beta(2) double knockout mice. Mol Pharmacol 2000 58 887 894
56. Devic E, Xiang Y, Gould D, Kobilka B, Beta-adrenergic receptor subtype-specific signaling in cardiac myocytes from beta(1) and beta(2) adrenoceptor knockout mice. Mol Pharmacol 2001 60 577 583
57. Long CS, Hartogensis WE, Simpson PC, Beta-adrenergic stimulation of cardiac non-myocytes augments the growth-promoting activity of non-myocyte conditioned medium. J Mol Cell Cardiol 1993 25 915 925. doi: 10.1006/jmcc.1993.1104.
58. Battich N, Stoeger T, Pelkmans L, Control of transcript variability in single mammalian cells. Cell 2015 163 1596 1610. doi: 10.1016/j.cell.2015.11.018.
59. Zhu WZ, Zheng M, Koch WJ, Lefkowitz RJ, Kobilka BK, Xiao RP, Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes. Proc Natl Acad Sci U S A 2001 98 1607 1612. doi: 10.1073/pnas.98.4.1607.
60. Belge C, Hammond J, Dubois-Deruy E, Enhanced expression of β3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase. Circulation 2014 129 451 462. doi: 10.1161/CIRCULATIONAHA.113.004940.
61. Altschuler SJ, Wu LF, Cellular heterogeneity: do differences make a difference? Cell 2010 141 559 563. doi: 10.1016/j.cell.2010.04.033.
62. Waspe LE, Ordahl CP, Simpson PC, The cardiac beta-myosin heavy chain isogene is induced selectively in alpha 1-adrenergic receptor-stimulated hypertrophy of cultured rat heart myocytes. J Clin Invest 1990 85 1206 1214. doi: 10.1172/JCI114554.
63. López JE, Myagmar BE, Swigart PM, Montgomery MD, Haynam S, Bigos M, Rodrigo MC, Simpson PC, β-myosin heavy chain is induced by pressure overload in a minor subpopulation of smaller mouse cardiac myocytes. Circ Res 2011 109 629 638. doi: 10.1161/CIRCRESAHA.111.243410.
64. Akhter SA, Milano CA, Shotwell KF, Cho MC, Rockman HA, Lefkowitz RJ, Koch WJ, Transgenic mice with cardiac overexpression of alpha1B-adrenergic receptors. In vivo alpha1-adrenergic receptor-mediated regulation of beta-adrenergic signaling. J Biol Chem 1997 272 21253 21259
65. Bristow MR, Feldman AM, Adams KF Jr, Goldstein S, Selective versus nonselective beta-blockade for heart failure therapy: are there lessons to be learned from the COMET trial? J Card Fail 2003 9 444 453
66. Jensen BC, Swigart PM, De Marco T, Hoopes C, Simpson PC, {alpha}1-Adrenergic receptor subtypes in nonfailing and failing human myocardium. Circ Heart Fail 2009 2 654 663
67. Fajardo G, Zhao M, Urashima T, Farahani S, Hu DQ, Reddy S, Bernstein D, Deletion of the β2-adrenergic receptor prevents the development of cardiomyopathy in mice. J Mol Cell Cardiol 2013 63 155 164. doi: 10.1016/j.yjmcc.2013.07.016.
68. Wang Q, Liu Y, Fu Q, Xu B, Zhang Y, Kim S, Tan R, Barbagallo F, West T, Anderson E, Wei W, Abel ED, Xiang YK, Inhibiting insulin-mediated beta2-adrenergic receptor activation prevents diabetes-associated cardiac dysfunction. 2017 135 73 88
69. Dash R, Chung J, Chan T, Yamada M, Barral J, Nishimura D, Yang PC, Simpson PC, A molecular MRI probe to detect treatment of cardiac apoptosis in vivo. Magn Reson Med 2011 66 1152 1162. doi: 10.1002/mrm.22876.
70. Wang GY, Yeh CC, Jensen BC, Mann MJ, Simpson PC, Baker AJ, Heart failure switches the RV alpha1-adrenergic inotropic response from negative to positive. Am J Physiol Heart Circ Physiol 2010 298 H913 H920. doi: 10.1152/ajpheart.00259.2009.
71. Stewart AF, Rokosh DG, Bailey BA, Karns LR, Chang KC, Long CS, Kariya K, Simpson PC, Cloning of the rat alpha 1C-adrenergic receptor from cardiac myocytes. alpha 1C, alpha 1B, and alpha 1D mRNAs are present in cardiac myocytes but not in cardiac fibroblasts. Circ Res 1994 75 796 802
72. Kraft T, Montag J, Radocaj A, Brenner B, Hypertrophic cardiomyopathy: cell-to-cell imbalance in gene expression and contraction force as trigger for disease phenotype development. Circ Res 2016 119 992 995. doi: 10.1161/CIRCRESAHA.116.309804.