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Annual Review of Physiology

Volume 84, 2022

Adrenergic Regulation of Calcium Channels in the Heart

Abstract

Each heartbeat is initiated by the action potential, an electrical signal that depolarizes the plasma membrane and activates a cycle of calcium influx via voltage-gated calcium channels, calcium release via ryanodine receptors, and calcium reuptake and efflux via calcium-ATPase pumps and sodium-calcium exchangers. Agonists of the sympathetic nervous system bind to adrenergic receptors in cardiomyocytes, which, via cascading signal transduction pathways and protein kinase A (PKA), increase the heart rate (chronotropy), the strength of myocardial contraction (inotropy), and the rate of myocardial relaxation (lusitropy). These effects correlate with increased intracellular concentration of calcium, which is required for the augmentation of cardiomyocyte contraction. Despite extensive investigations, the molecular mechanisms underlying sympathetic nervous system regulation of calcium influx in cardiomyocytes have remained elusive over the last 40 years. Recent studies have uncovered the mechanisms underlying this fundamental biologic process, namely that PKA phosphorylates a calcium channel inhibitor, Rad, thereby releasing inhibition and increasing calcium influx. Here, we describe an updated model for how signals from adrenergic agonists are transduced to stimulate calcium influx and contractility in the heart.

Keyword(s): calcium channel, excitation-contraction coupling, heart, phosphorylation, sympathetic nervous system
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/content/journals/10.1146/annurev-physiol-060121-041653
2022-02-10
2024-05-02
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Literature Cited

  1. 1. 
    Moore B. 1911. In memory of Sidney Ringer [1835–1910]: some account of the fundamental discoveries of the great pioneer of the bio-chemistry of crystallo-colloids in living cells. Biochem. J. 5:ib3–xix
     [Google Scholar]
  2. 2. 
    Fabiato A, Fabiato F. 1975. Contractions induced by a calcium-triggered release of calcium from the sarcoplasmic reticulum of single skinned cardiac cells. J. Physiol. 249:469–95
     [Google Scholar]
  3. 3. 
    Fabiato A, Fabiato F. 1979. Calcium and cardiac excitation-contraction coupling. Annu. Rev. Physiol. 41:473–84
     [Google Scholar]
  4. 4. 
    Bers DM. 2002. Cardiac excitation-contraction coupling. Nature 415:198–205
     [Google Scholar]
  5. 5. 
    Tsien RW, Bean BP, Hess P, Lansman JB, Nilius B, Nowycky MC 1986. Mechanisms of calcium channel modulation by β-adrenergic agents and dihydropyridine calcium agonists. J. Mol. Cell. Cardiol. 18:691–710
     [Google Scholar]
  6. 6. 
    Lindemann JP, Jones LR, Hathaway DR, Henry BG, Watanabe AM. 1983. β-Adrenergic stimulation of phospholamban phosphorylation and Ca2+-ATPase activity in guinea pig ventricles. J. Biol. Chem. 258:464–71
     [Google Scholar]
  7. 7. 
    Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D et al. 2000. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101:365–76
     [Google Scholar]
  8. 8. 
    Wehrens XH, Lehnart SE, Huang F, Vest JA, Reiken SR et al. 2003. FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell 113:829–40
     [Google Scholar]
  9. 9. 
    Shan J, Kushnir A, Betzenhauser MJ, Reiken S, Li J et al. 2010. Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice. J. Clin. Investig. 120:4388–98
     [Google Scholar]
  10. 10. 
    Potenza DM, Janicek R, Fernandez-Tenorio M, Camors E, Ramos-Mondragon R et al. 2019. Phosphorylation of the ryanodine receptor 2 at serine 2030 is required for a complete β-adrenergic response. J. Gen. Physiol. 151:131–45
     [Google Scholar]
  11. 11. 
    Chen YH, Li MH, Zhang Y, He LL, Yamada Y et al. 2004. Structural basis of the α1-β subunit interaction of voltage-gated Ca2+ channels. Nature 429:675–80
     [Google Scholar]
  12. 12. 
    Opatowsky Y, Chen CC, Campbell KP, Hirsch JA. 2004. Structural analysis of the voltage-dependent calcium channel β subunit functional core and its complex with the α1 interaction domain. Neuron 42:387–99
     [Google Scholar]
  13. 13. 
    Van Petegem F, Clark KA, Chatelain FC, Minor DLJr 2004. Structure of a complex between a voltage-gated calcium channel β-subunit and an α-subunit domain. Nature 429:671–75
     [Google Scholar]
  14. 14. 
    Oliver G, Schäfer EA. 1895. The physiological effects of extracts of the suprarenal capsules. J. Physiol. 18:230–76
     [Google Scholar]
  15. 15. 
    Cannon WB. 1915. Bodily Changes in Pain, Hunger, Fear and Rage: An Account of Recent Researches into the Function of Emotional Excitement New York: D Appleton & Co.
  16. 16. 
    Snyder SH. 2006. Turning off neurotransmitters. Cell 125:13–15
     [Google Scholar]
  17. 17. 
    Moran NC, Perkins ME. 1958. Adrenergic blockade of the mammalian heart by a dichloro analogue of isoproterenol. J. Pharmacol. Exp. Ther. 124:223–37
     [Google Scholar]
  18. 18. 
    Powell CE, Slater IH. 1958. Blocking of inhibitory adrenergic receptors by a dichloro analog of isoproterenol. J. Pharmacol. Exp. Ther. 122:480–88
     [Google Scholar]
  19. 19. 
    Black JW, Crowther AF, Shanks RG, Smith LH, Dornhorst AC. 1964. A new adrenergic β-receptor antagonist. Lancet 1:1080–81
     [Google Scholar]
  20. 20. 
    Sutherland EW. 1972. Studies on the mechanism of hormone action. Science 177:401–8
     [Google Scholar]
  21. 21. 
    Kobilka BK, Kobilka TS, Daniel K, Regan JW, Caron MG, Lefkowitz RJ 1988. Chimeric α2-, β2-adrenergic receptors: delineation of domains involved in effector coupling and ligand binding specificity. Science 240:1310–16
     [Google Scholar]
  22. 22. 
    Shannon TR, Ginsburg KS, Bers DM. 2002. Quantitative assessment of the SR Ca2+ leak-load relationship. Circ. Res. 91:594–600
     [Google Scholar]
  23. 23. 
    Hunter DR, Haworth RA, Berkoff HA. 1983. Modulation of cellular calcium stores in the perfused rat heart by isoproterenol and ryanodine. Circ. Res. 53:703–12
     [Google Scholar]
  24. 24. 
    Rosas PC, Liu Y, Abdalla MI, Thomas CM, Kidwell DT et al. 2015. Phosphorylation of cardiac myosin-binding protein-C is a critical mediator of diastolic function. Circ. Heart Fail. 8:582–94
     [Google Scholar]
  25. 25. 
    Li L, Desantiago J, Chu G, Kranias EG, Bers DM. 2000. Phosphorylation of phospholamban and troponin I in β-adrenergic-induced acceleration of cardiac relaxation. Am. J. Physiol. Heart Circ. Physiol. 278:H769–79
     [Google Scholar]
  26. 26. 
    Tong CW, Wu X, Liu Y, Rosas PC, Sadayappan S et al. 2015. Phosphoregulation of cardiac inotropy via myosin binding protein-C during increased pacing frequency or β1-adrenergic stimulation. Circ. Heart Fail. 8:595–604
     [Google Scholar]
  27. 27. 
    Mangoni ME, Nargeot J. 2008. Genesis and regulation of the heart automaticity. Physiol. Rev. 88:919–82
     [Google Scholar]
  28. 28. 
    Zaza A, Robinson RB, DiFrancesco D 1996. Basal responses of the L-type Ca2+ and hyperpolarization-activated currents to autonomic agonists in the rabbit sino-atrial node. J. Physiol. 491:Part 2347–55
     [Google Scholar]
  29. 29. 
    Choate JK, Feldman R. 2003. Neuronal control of heart rate in isolated mouse atria. Am. J. Physiol. Heart Circ. Physiol. 285:H1340–46
     [Google Scholar]
  30. 30. 
    Matthes J, Huber I, Haaf O, Antepohl W, Striessnig J, Herzig S. 2000. Pharmacodynamic interaction between mibefradil and other calcium channel blockers. Naunyn-Schmiedebergs Arch. Pharmacol. 361:578–83
     [Google Scholar]
  31. 31. 
    Rigg L, Heath BM, Cui Y, Terrar DA. 2000. Localisation and functional significance of ryanodine receptors during β-adrenoceptor stimulation in the guinea-pig sino-atrial node. Cardiovasc. Res. 48:254–64
     [Google Scholar]
  32. 32. 
    Vinogradova TM, Bogdanov KY, Lakatta EG. 2002. β-Adrenergic stimulation modulates ryanodine receptor Ca2+ release during diastolic depolarization to accelerate pacemaker activity in rabbit sinoatrial nodal cells. Circ. Res. 90:73–79
     [Google Scholar]
  33. 33. 
    Marx SO, Kurokawa J, Reiken S, Motoike H, D'Armiento J et al. 2002. Requirement of a macromolecular signaling complex for β adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science 295:496–99
     [Google Scholar]
  34. 34. 
    Yue DT, Herzig S, Marban E. 1990. β-Adrenergic stimulation of calcium channels occurs by potentiation of high-activity gating modes. PNAS 87:753–57
     [Google Scholar]
  35. 35. 
    Hirano Y, Suzuki K, Yamawake N, Hiraoka M 1994. Multiple kinetic effects of β-adrenergic stimulation on single cardiac L-type Ca channels. Am. J. Physiol. 266:C1714–21
     [Google Scholar]
  36. 36. 
    Herzig S, Patil P, Neumann J, Staschen CM, Yue DT. 1993. Mechanisms of β-adrenergic stimulation of cardiac Ca2+ channels revealed by discrete-time Markov analysis of slow gating. Biophys. J. 65:1599–612
     [Google Scholar]
  37. 37. 
    Hess P, Lansman JB, Tsien RW. 1984. Different modes of Ca channel gating behaviour favoured by dihydropyridine Ca agonists and antagonists. Nature 311:538–44
     [Google Scholar]
  38. 38. 
    Del Villar SG, Voelker TL, Westhoff M, Reddy GR, Spooner HC et al. 2021. β-Adrenergic control of sarcolemmal CaV1.2 abundance by small GTPase Rab proteins. PNAS 118:e2017937118
     [Google Scholar]
  39. 39. 
    Chang FC, Hosey MM. 1988. Dihydropyridine and phenylalkylamine receptors associated with cardiac and skeletal muscle calcium channels are structurally different. J. Biol. Chem. 263:18929–37
     [Google Scholar]
  40. 40. 
    Yoshida A, Takahashi M, Fujimoto Y, Takisawa H, Nakamura T. 1990. Molecular characterization of 1,4-dihydropyridine-sensitive calcium channels of chick heart and skeletal muscle. J. Biochem. 107:608–12
     [Google Scholar]
  41. 41. 
    Yoshida A, Takahashi M, Nishimura S, Takeshima H, Kokubun S. 1992. Cyclic AMP-dependent phosphorylation and regulation of the cardiac dihydropyridine-sensitive Ca channel. FEBS Lett 309:343–49
     [Google Scholar]
  42. 42. 
    De Jongh KS, Murphy BJ, Colvin AA, Hell JW, Takahashi M, Catterall WA. 1996. Specific phosphorylation of a site in the full-length form of the α1 subunit of the cardiac L-type calcium channel by adenosine 3′,5′-cyclic monophosphate-dependent protein kinase. Biochemistry 35:10392–402
     [Google Scholar]
  43. 43. 
    Mitterdorfer J, Froschmayr M, Grabner M, Moebius FF, Glossmann H, Striessnig J. 1996. Identification of PK-A phosphorylation sites in the carboxyl terminus of L-type calcium channel α1 subunits. Biochemistry 35:9400–6
     [Google Scholar]
  44. 44. 
    Hulme JT, Westenbroek RE, Scheuer T, Catterall WA. 2006. Phosphorylation of serine 1928 in the distal C-terminal domain of cardiac CaV1.2 channels during β1-adrenergic regulation. PNAS 103:16574–79
     [Google Scholar]
  45. 45. 
    Gao T, Yatani A, Dell'Acqua ML, Sako H, Green SA et al. 1997. cAMP-dependent regulation of cardiac L-type Ca2+ channels requires membrane targeting of PKA and phosphorylation of channel subunits. Neuron 19:185–96
     [Google Scholar]
  46. 46. 
    Naguro I, Nagao T, Adachi-Akahane S. 2001. Ser1901 of α1C subunit is required for the PKA-mediated enhancement of L-type Ca2+ channel currents but not for the negative shift of activation. FEBS Lett 489:87–91
     [Google Scholar]
  47. 47. 
    Bunemann M, Gerhardstein BL, Gao T, Hosey MM. 1999. Functional regulation of L-type calcium channels via protein kinase A-mediated phosphorylation of the β2 subunit. J. Biol. Chem. 274:33851–54
     [Google Scholar]
  48. 48. 
    Haase H, Bartel S, Karczewski P, Morano I, Krause EG 1996. In-vivo phosphorylation of the cardiac L-type calcium channel β-subunit in response to catecholamines. Mol. Cell. Biochem. 163–164:99–106
     [Google Scholar]
  49. 49. 
    Ganesan AN, Maack C, Johns DC, Sidor A, O'Rourke B. 2006. β-Adrenergic stimulation of L-type Ca2+ channels in cardiac myocytes requires the distal carboxyl terminus of α1C but not serine 1928. Circ. Res. 98:e11–8
     [Google Scholar]
  50. 50. 
    Miriyala J, Nguyen T, Yue DT, Colecraft HM. 2008. Role of CaVβ subunits, and lack of functional reserve, in protein kinase A modulation of cardiac CaV1.2 channels. Circ. Res. 102:e54–64
     [Google Scholar]
  51. 51. 
    Lemke T, Welling A, Christel CJ, Blaich A, Bernhard D et al. 2008. Unchanged β-adrenergic stimulation of cardiac L-type calcium channels in Cav1.2 phosphorylation site S1928A mutant mice. J. Biol. Chem. 283:34738–44
     [Google Scholar]
  52. 52. 
    Brandmayr J, Poomvanicha M, Domes K, Ding J, Blaich A et al. 2012. Deletion of the C-terminal phosphorylation sites in the cardiac β-subunit does not affect the basic β-adrenergic response of the heart and the Cav1.2 channel. J. Biol. Chem. 287:22584–92
     [Google Scholar]
  53. 53. 
    Fuller MD, Emrick MA, Sadilek M, Scheuer T, Catterall WA. 2010. Molecular mechanism of calcium channel regulation in the fight-or-flight response. Sci. Signal. 3:ra70
     [Google Scholar]
  54. 54. 
    Beetz N, Hein L, Meszaros J, Gilsbach R, Barreto F et al. 2009. Transgenic simulation of human heart failure-like L-type Ca2+-channels: implications for fibrosis and heart rate in mice. Cardiovasc. Res. 84:396–406
     [Google Scholar]
  55. 55. 
    Muth JN, Yamaguchi H, Mikala G, Grupp IL, Lewis W et al. 1999. Cardiac-specific overexpression of the α1 subunit of the L-type voltage-dependent Ca2+ channel in transgenic mice. Loss of isoproterenol-induced contraction. J. Biol. Chem. 274:21503–6
     [Google Scholar]
  56. 56. 
    Groner F, Rubio M, Schulte-Euler P, Matthes J, Khan IF et al. 2004. Single-channel gating and regulation of human L-type calcium channels in cardiomyocytes of transgenic mice. Biochem. Biophys. Res. Commun. 314:878–84
     [Google Scholar]
  57. 57. 
    Tang M, Zhang X, Li Y, Guan Y, Ai X et al. 2010. Enhanced basal contractility but reduced excitation-contraction coupling efficiency and β-adrenergic reserve of hearts with increased Cav1.2 activity. Am. J. Physiol. Heart Circ. Physiol. 299:H519–28
     [Google Scholar]
  58. 58. 
    Chen X, Zhang X, Kubo H, Harris DM, Mills GD et al. 2005. Ca2+ influx-induced sarcoplasmic reticulum Ca2+ overload causes mitochondrial-dependent apoptosis in ventricular myocytes. Circ. Res. 97:1009–17
     [Google Scholar]
  59. 59. 
    Chen X, Nakayama H, Zhang X, Ai X, Harris DM et al. 2011. Calcium influx through Cav1.2 is a proximal signal for pathological cardiomyocyte hypertrophy. J. Mol. Cell. Cardiol. 50:460–70
     [Google Scholar]
  60. 60. 
    Wang S, Ziman B, Bodi I, Rubio M, Zhou YY et al. 2009. Dilated cardiomyopathy with increased SR Ca2+ loading preceded by a hypercontractile state and diastolic failure in the α1CTG mouse. PLOS ONE 4:e4133
     [Google Scholar]
  61. 61. 
    Yang L, Katchman A, Samad T, Morrow J, Weinberg R, Marx SO. 2013. β-Adrenergic regulation of the L-type Ca2+ channel does not require phosphorylation of α1C Ser1700. Circ. Res. 113:871–80
     [Google Scholar]
  62. 62. 
    Wan E, Abrams J, Weinberg RL, Katchman AN, Bayne J et al. 2016. Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice. J. Clin. Investig. 126:112–22
     [Google Scholar]
  63. 63. 
    Avula UMR, Abrams J, Katchman A, Zakharov S, Mironov S et al. 2019. Heterogeneity of the action potential duration is required for sustained atrial fibrillation. JCI Insight 4:e128765
     [Google Scholar]
  64. 64. 
    Abrams J, Roybal D, Chakouri N, Katchman AN, Weinberg R et al. 2020. Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding-deficient channels. JCI Insight 5:e141736
     [Google Scholar]
  65. 65. 
    Fu Y, Westenbroek RE, Scheuer T, Catterall WA. 2014. Basal and β-adrenergic regulation of the cardiac calcium channel CaV1.2 requires phosphorylation of serine 1700. PNAS 111:16598–603
     [Google Scholar]
  66. 66. 
    Fu Y, Westenbroek RE, Scheuer T, Catterall WA. 2013. Phosphorylation sites required for regulation of cardiac calcium channels in the fight-or-flight response. PNAS 110:19621–26
     [Google Scholar]
  67. 67. 
    Poomvanicha M, Matthes J, Domes K, Patrucco E, Angermeier E et al. 2017. β-Adrenergic regulation of the heart expressing the Ser1700A/Thr1704A mutated Cav1.2 channel. J. Mol. Cell. Cardiol. 111:10–16
     [Google Scholar]
  68. 68. 
    Liu G, Papa A, Katchman AN, Zakharov SI, Roybal D et al. 2020. Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics. Nature 577:695–700
     [Google Scholar]
  69. 69. 
    Yang L, Katchman A, Kushner J, Kushnir A, Zakharov SI et al. 2019. Cardiac CaV1.2 channels require β subunits for β-adrenergic-mediated modulation but not trafficking. J. Clin. Investig. 129:647–58
     [Google Scholar]
  70. 70. 
    Katchman A, Yang L, Zakharov SI, Kushner J, Abrams J et al. 2017. Proteolytic cleavage and PKA phosphorylation of α1C subunit are not required for adrenergic regulation of CaV1.2 in the heart. PNAS 114:9194–99
     [Google Scholar]
  71. 71. 
    Weissgerber P, Held B, Bloch W, Kaestner L, Chien KR et al. 2006. Reduced cardiac L-type Ca2+ current in CaVβ2−/− embryos impairs cardiac development and contraction with secondary defects in vascular maturation. Circ. Res. 99:749–57
     [Google Scholar]
  72. 72. 
    Perez-Reyes E, Castellano A, Kim HS, Bertrand P, Baggstrom E et al. 1992. Cloning and expression of a cardiac/brain β subunit of the L-type calcium channel. J. Biol. Chem. 267:1792–97
     [Google Scholar]
  73. 73. 
    Singer D, Biel M, Lotan I, Flockerzi V, Hofmann F, Dascal N. 1991. The roles of the subunits in the function of the calcium channel. Science 253:1553–57
     [Google Scholar]
  74. 74. 
    Buraei Z, Yang J. 2010. The β subunit of voltage-gated Ca2+ channels. Physiol. Rev. 90:1461–506
     [Google Scholar]
  75. 75. 
    Takahashi SX, Miriyala J, Colecraft HM. 2004. Membrane-associated guanylate kinase-like properties of β-subunits required for modulation of voltage-dependent Ca2+ channels. PNAS 101:7193–98
     [Google Scholar]
  76. 76. 
    Meissner M, Weissgerber P, Londono JE, Prenen J, Link S et al. 2011. Moderate calcium channel dysfunction in adult mice with inducible cardiomyocyte-specific excision of the cacnb2 gene. J. Biol. Chem. 286:15875–82
     [Google Scholar]
  77. 77. 
    Van Petegem F, Duderstadt KE, Clark KA, Wang M, Minor DLJr. 2008. Alanine-scanning mutagenesis defines a conserved energetic hotspot in the CaVα1 AID-CaVβ interaction site that is critical for channel modulation. Structure 16:280–94
     [Google Scholar]
  78. 78. 
    Papa A, Kushner J, Hennessey JA, Katchman AN, Zakharov SI et al. 2021. Adrenergic CaV1.2 activation via rad phosphorylation converges at α1C I-II loop. Circ. Res. 128:76–88
     [Google Scholar]
  79. 79. 
    Negroni JA, Morotti S, Lascano EC, Gomes AV, Grandi E et al. 2015. β-Adrenergic effects on cardiac myofilaments and contraction in an integrated rabbit ventricular myocyte model. J. Mol. Cell. Cardiol. 81:162–75
     [Google Scholar]
  80. 80. 
    Bondarenko VE. 2014. A compartmentalized mathematical model of the β1-adrenergic signaling system in mouse ventricular myocytes. PLOS ONE 9:e89113
     [Google Scholar]
  81. 81. 
    Mullins PD, Bondarenko VE. 2020. Mathematical model for β1-adrenergic regulation of the mouse ventricular myocyte contraction. Am. J. Physiol. Heart Circ. Physiol. 318:H264–82
     [Google Scholar]
  82. 82. 
    Morotti S, Edwards AG, McCulloch AD, Bers DM, Grandi E. 2014. A novel computational model of mouse myocyte electrophysiology to assess the synergy between Na+ loading and CaMKII. J. Physiol. 592:1181–97
     [Google Scholar]
  83. 83. 
    Hell JW, Westenbroek RE, Warner C, Ahlijanian MK, Prystay W et al. 1993. Identification and differential subcellular localization of the neuronal class C and class D L-type calcium channel α1 subunits. J. Cell Biol. 123:949–62
     [Google Scholar]
  84. 84. 
    De Jongh KS, Warner C, Colvin AA, Catterall WA. 1991. Characterization of the two size forms of the α1 subunit of skeletal muscle L-type calcium channels. PNAS 88:10778–82
     [Google Scholar]
  85. 85. 
    Hulme JT, Konoki K, Lin TW, Gritsenko MA, Camp DG2nd et al. 2005. Sites of proteolytic processing and noncovalent association of the distal C-terminal domain of CaV1.1 channels in skeletal muscle. PNAS 102:5274–79
     [Google Scholar]
  86. 86. 
    Weiss S, Oz S, Benmocha A, Dascal N. 2013. Regulation of cardiac L-type Ca2+ channel CaV1.2 via the β-adrenergic-cAMP-protein kinase A pathway: old dogmas, advances, and new uncertainties. Circ. Res. 113:617–31
     [Google Scholar]
  87. 87. 
    Dai S, Hall DD, Hell JW. 2009. Supramolecular assemblies and localized regulation of voltage-gated ion channels. Physiol. Rev. 89:411–52
     [Google Scholar]
  88. 88. 
    Gao T, Cuadra AE, Ma H, Bunemann M, Gerhardstein BL et al. 2001. C-terminal fragments of the α1C (CaV1.2) subunit associate with and regulate L-type calcium channels containing C-terminal-truncated α1C subunits. J. Biol. Chem. 276:21089–97
     [Google Scholar]
  89. 89. 
    Hulme JT, Yarov-Yarovoy V, Lin TW, Scheuer T, Catterall WA. 2006. Autoinhibitory control of the CaV1.2 channel by its proteolytically processed distal C-terminal domain. J. Physiol. 576:87–102
     [Google Scholar]
  90. 90. 
    Bannister JP, Leo MD, Narayanan D, Jangsangthong W, Nair A et al. 2013. The voltage-dependent L-type Ca2+ (CaV1.2) channel C-terminus fragment is a bi-modal vasodilator. J. Physiol. 591:2987–98
     [Google Scholar]
  91. 91. 
    Gomez-Ospina N, Tsuruta F, Barreto-Chang O, Hu L, Dolmetsch R. 2006. The C terminus of the L-type voltage-gated calcium channel CaV1.2 encodes a transcription factor. Cell 127:591–606
     [Google Scholar]
  92. 92. 
    Schroder E, Byse M, Satin J. 2009. L-type calcium channel C terminus autoregulates transcription. Circ. Res. 104:1373–81
     [Google Scholar]
  93. 93. 
    Gerhardstein BL, Gao T, Bunemann M, Puri TS, Adair A et al. 2000. Proteolytic processing of the C terminus of the α1C subunit of L-type calcium channels and the role of a proline-rich domain in membrane tethering of proteolytic fragments. J. Biol. Chem. 275:8556–63
     [Google Scholar]
  94. 94. 
    Catterall WA. 2015. Regulation of cardiac calcium channels in the fight-or-flight response. Curr. Mol. Pharmacol. 8:12–21
     [Google Scholar]
  95. 95. 
    Oz S, Pankonien I, Belkacemi A, Flockerzi V, Klussmann E et al. 2017. Protein kinase A regulates C-terminally truncated CaV1.2 in Xenopus oocytes: roles of N- and C-termini of the α1C subunit. J. Physiol. 595:3181–202
     [Google Scholar]
  96. 96. 
    De Jongh KS, Merrick DK, Catterall WA 1989. Subunits of purified calcium channels: a 212-kDa form of α1 and partial amino acid sequence of a phosphorylation site of an independent β subunit. PNAS 86:8585–89
     [Google Scholar]
  97. 97. 
    Gao T, Puri TS, Gerhardstein BL, Chien AJ, Green RD, Hosey MM. 1997. Identification and subcellular localization of the subunits of L-type calcium channels and adenylyl cyclase in cardiac myocytes. J. Biol. Chem. 272:19401–7
     [Google Scholar]
  98. 98. 
    Fu Y, Westenbroek RE, Yu FH, Clark JP3rd, Marshall MR et al. 2011. Deletion of the distal C terminus of CaV1.2 channels leads to loss of β-adrenergic regulation and heart failure in vivo. J. Biol. Chem. 286:12617–26
     [Google Scholar]
  99. 99. 
    Domes K, Ding J, Lemke T, Blaich A, Wegener JW et al. 2011. Truncation of murine CaV1.2 at Asp-1904 results in heart failure after birth. J. Biol. Chem. 286:33863–71
     [Google Scholar]
  100. 100. 
    Pawson T, Scott JD. 1997. Signaling through scaffold, anchoring, and adaptor proteins. Science 278:2075–80
     [Google Scholar]
  101. 101. 
    Leroy J, Abi-Gerges A, Nikolaev VO, Richter W, Lechene P et al. 2008. Spatiotemporal dynamics of β-adrenergic cAMP signals and L-type Ca2+ channel regulation in adult rat ventricular myocytes: role of phosphodiesterases. Circ. Res. 102:1091–100
     [Google Scholar]
  102. 102. 
    Hundsrucker C, Rosenthal W, Klussmann E. 2006. Peptides for disruption of PKA anchoring. Biochem. Soc. Trans. 34:472–73
     [Google Scholar]
  103. 103. 
    Hundsrucker C, Krause G, Beyermann M, Prinz A, Zimmermann B et al. 2006. High-affinity AKAP7δ-protein kinase A interaction yields novel protein kinase A-anchoring disruptor peptides. Biochem. J. 396:297–306
     [Google Scholar]
  104. 104. 
    Hulme JT, Lin TW, Westenbroek RE, Scheuer T, Catterall WA. 2003. β-Adrenergic regulation requires direct anchoring of PKA to cardiac CaV1.2 channels via a leucine zipper interaction with A kinase-anchoring protein 15. PNAS 100:13093–98
     [Google Scholar]
  105. 105. 
    Hall DD, Davare MA, Shi M, Allen ML, Weisenhaus M et al. 2007. Critical role of cAMP-dependent protein kinase anchoring to the L-type calcium channel Cav1.2 via A-kinase anchor protein 150 in neurons. Biochemistry 46:1635–46
     [Google Scholar]
  106. 106. 
    Nystoriak MA, Nieves-Cintron M, Patriarchi T, Buonarati OR, Prada MP et al. 2017. Ser1928 phosphorylation by PKA stimulates the L-type Ca2+ channel CaV1.2 and vasoconstriction during acute hyperglycemia and diabetes. Sci. Signal. 10:eaaf9647
     [Google Scholar]
  107. 107. 
    Murphy JG, Sanderson JL, Gorski JA, Scott JD, Catterall WA et al. 2014. AKAP-anchored PKA maintains neuronal L-type calcium channel activity and NFAT transcriptional signaling. 71577–88
  108. 108. 
    Nichols CB, Rossow CF, Navedo MF, Westenbroek RE, Catterall WA et al. 2010. Sympathetic stimulation of adult cardiomyocytes requires association of AKAP5 with a subpopulation of L-type calcium channels. Circ. Res. 107:747–56
     [Google Scholar]
  109. 109. 
    Jones BW, Brunet S, Gilbert ML, Nichols CB, Su T et al. 2012. Cardiomyocytes from AKAP7 knockout mice respond normally to adrenergic stimulation. PNAS 109:17099–104
     [Google Scholar]
  110. 110. 
    Yu H, Yuan C, Westenbroek RE, Catterall WA. 2018. The AKAP Cypher/Zasp contributes to β-adrenergic/PKA stimulation of cardiac CaV1.2 calcium channels. J. Gen. Physiol. 150:883–89
     [Google Scholar]
  111. 111. 
    Rees JS, Li XW, Perrett S, Lilley KS, Jackson AP. 2015. Protein neighbors and proximity proteomics. Mol. Cell. Proteom. 14:2848–56
     [Google Scholar]
  112. 112. 
    Hung V, Zou P, Rhee HW, Udeshi ND, Cracan V et al. 2014. Proteomic mapping of the human mitochondrial intermembrane space in live cells via ratiometric APEX tagging. Mol. Cell 55:332–41
     [Google Scholar]
  113. 113. 
    Hung V, Udeshi ND, Lam SS, Loh KH, Cox KJ et al. 2016. Spatially resolved proteomic mapping in living cells with the engineered peroxidase APEX2. Nat. Protoc. 11:456–75
     [Google Scholar]
  114. 114. 
    Rhee HW, Zou P, Udeshi ND, Martell JD, Mootha VK et al. 2013. Proteomic mapping of mitochondria in living cells via spatially restricted enzymatic tagging. Science 339:1328–31
     [Google Scholar]
  115. 115. 
    Paek J, Kalocsay M, Staus DP, Wingler L, Pascolutti R et al. 2017. Multidimensional tracking of GPCR signaling via peroxidase-catalyzed proximity labeling. Cell 169:338–49 e11
     [Google Scholar]
  116. 116. 
    Cho KF, Branon TC, Udeshi ND, Myers SA, Carr SA, Ting AY. 2020. Proximity labeling in mammalian cells with TurboID and split-TurboID. Nat. Protoc. 15:3971–99
     [Google Scholar]
  117. 117. 
    Cho KF, Branon TC, Rajeev S, Svinkina T, Udeshi ND et al. 2020. Split-TurboID enables contact-dependent proximity labeling in cells. PNAS 117:12143–54
     [Google Scholar]
  118. 118. 
    Branon TC, Bosch JA, Sanchez AD, Udeshi ND, Svinkina T et al. 2018. Efficient proximity labeling in living cells and organisms with TurboID. Nat. Biotechnol. 36:880–87
     [Google Scholar]
  119. 119. 
    Han S, Li J, Ting AY 2018. Proximity labeling: spatially resolved proteomic mapping for neurobiology. Curr. Opin. Neurobiol. 50:17–23
     [Google Scholar]
  120. 120. 
    Lam SS, Martell JD, Kamer KJ, Deerinck TJ, Ellisman MH et al. 2015. Directed evolution of APEX2 for electron microscopy and proximity labeling. Nat. Methods 12:51–54
     [Google Scholar]
  121. 121. 
    Martell JD, Deerinck TJ, Sancak Y, Poulos TL, Mootha VK et al. 2012. Engineered ascorbate peroxidase as a genetically encoded reporter for electron microscopy. Nat. Biotechnol. 30:1143–48
     [Google Scholar]
  122. 122. 
    Beguin P, Nagashima K, Gonoi T, Shibasaki T, Takahashi K et al. 2001. Regulation of Ca2+ channel expression at the cell surface by the small G-protein kir/Gem. Nature 411:701–6
     [Google Scholar]
  123. 123. 
    Colecraft HM. 2020. Designer genetically encoded voltage-dependent calcium channel inhibitors inspired by RGK GTPases. J. Physiol. 598:1683–93
     [Google Scholar]
  124. 124. 
    Finlin BS, Crump SM, Satin J, Andres DA. 2003. Regulation of voltage-gated calcium channel activity by the Rem and Rad GTPases. PNAS 100:14469–74
     [Google Scholar]
  125. 125. 
    Flynn R, Zamponi GW 2010. Regulation of calcium channels by RGK proteins. Channels 4:434–39
     [Google Scholar]
  126. 126. 
    Buraei Z, Yang J. 2015. Inhibition of voltage-gated calcium channels by RGK proteins. Curr. Mol. Pharmacol. 8:180–87
     [Google Scholar]
  127. 127. 
    Puhl HL3rd, Lu VB, Won YJ, Sasson Y, Hirsch JA et al. 2014. Ancient origins of RGK protein function: modulation of voltage-gated calcium channels preceded the protostome and deuterostome split. PLOS ONE 9:e100694
     [Google Scholar]
  128. 128. 
    Reynet C, Kahn CR. 1993. Rad: a member of the Ras family overexpressed in muscle of type II diabetic humans. Science 262:1441–44
     [Google Scholar]
  129. 129. 
    Manning JR, Yin G, Kaminski CN, Magyar J, Feng HZ et al. 2013. Rad GTPase deletion increases L-type calcium channel current leading to increased cardiac contraction. J. Am. Heart Assoc. 2:e000459
     [Google Scholar]
  130. 130. 
    Levitan BM, Manning JR, Withers CN, Smith JD, Shaw RM et al. 2016. Rad-deletion phenocopies tonic sympathetic stimulation of the heart. J. Cardiovasc. Transl. Res. 9:432–44
     [Google Scholar]
  131. 131. 
    Ahern BM, Levitan BM, Veeranki S, Shah M, Ali N et al. 2019. Myocardial-restricted ablation of the GTPase RAD results in a pro-adaptive heart response in mice. J. Biol. Chem. 294:10913–27
     [Google Scholar]
  132. 132. 
    Levitan BM, Ahern BM, Aloysius A, Brown L, Wen Y et al. 2021. Rad-GTPase contributes to heart rate via L-type calcium channel regulation. J. Mol. Cell. Cardiol. 154:60–69
     [Google Scholar]
  133. 133. 
    Chang L, Zhang J, Tseng YH, Xie CQ, Ilany J et al. 2007. Rad GTPase deficiency leads to cardiac hypertrophy. Circulation 116:2976–83
     [Google Scholar]
  134. 134. 
    Manning JR, Withers CN, Levitan B, Smith JD, Andres DA, Satin J 2015. Loss of Rad-GTPase produces a novel adaptive cardiac phenotype resistant to systolic decline with aging. Am. J. Physiol. Heart Circ. Physiol. 309:H1336–45
     [Google Scholar]
  135. 135. 
    Li Y, Chang Y, Li X, Li X, Gao J et al. 2020. RAD-deficient human cardiomyocytes develop hypertrophic cardiomyopathy phenotypes due to calcium dysregulation. Front. Cell Dev. Biol. 8:585879
     [Google Scholar]
  136. 136. 
    Wang X, Tsien RW 2020. Suspect that modulates the heartbeat is ensnared. Nature 577:624–26
     [Google Scholar]
  137. 137. 
    Moyers JS, Zhu J, Kahn CR. 1998. Effects of phosphorylation on function of the Rad GTPase. Biochem. J. 333:Part 3609–14
     [Google Scholar]
  138. 138. 
    Yang T, Puckerin A, Colecraft HM 2012. Distinct RGK GTPases differentially use α1- and auxiliary β-binding-dependent mechanisms to inhibit CaV1.2/CaV2.2 channels. PLOS ONE 7:e37079
     [Google Scholar]
  139. 139. 
    Arias JM, Murbartian J, Vitko I, Lee JH, Perez-Reyes E. 2005. Transfer of β subunit regulation from high to low voltage-gated Ca2+ channels. FEBS Lett 579:3907–12
     [Google Scholar]
  140. 140. 
    Findeisen F, Minor DL Jr 2009. Disruption of the IS6-AID linker affects voltage-gated calcium channel inactivation and facilitation. J. Gen. Physiol. 133:327–43
     [Google Scholar]
  141. 141. 
    Mangoni ME, Couette B, Bourinet E, Platzer J, Reimer D et al. 2003. Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity. PNAS 100:5543–48
     [Google Scholar]
  142. 142. 
    Mahapatra S, Marcantoni A, Zuccotti A, Carabelli V, Carbone E 2012. Equal sensitivity of Cav1.2 and Cav1.3 channels to the opposing modulations of PKA and PKG in mouse chromaffin cells. J. Physiol. 590:5053–73
     [Google Scholar]
  143. 143. 
    Katz M, Subramaniam S, Chomsky-Hecht O, Tsemakhovich V, Flockerzi V et al. 2021. Reconstitution of β-adrenergic regulation of CaV1.2: Rad-dependent and Rad-independent protein kinase A mechanisms. PNAS 118:e2100021118
     [Google Scholar]
  144. 144. 
    Man KNM, Bartels P, Horne MC, Hell JW. 2020. Tissue-specific adrenergic regulation of the L-type Ca2+ channel CaV1.2. Sci. Signal. 13:eabc6438
     [Google Scholar]
  145. 145. 
    Qian H, Patriarchi T, Price JL, Matt L, Lee B et al. 2017. Phosphorylation of Ser1928 mediates the enhanced activity of the L-type Ca2+ channel Cav1.2 by the β2-adrenergic receptor in neurons. Sci. Signal. 10:eaaf9659
     [Google Scholar]
  146. 146. 
    Prada MP, Syed AU, Buonarati OR, Reddy GR, Nystoriak MA et al. 2019. A Gs-coupled purinergic receptor boosts Ca2+ influx and vascular contractility during diabetic hyperglycemia. eLife 8:e42214
     [Google Scholar]
  147. 147. 
    Hambleton M, York A, Sargent MA, Kaiser RA, Lorenz JN et al. 2007. Inducible and myocyte-specific inhibition of PKCα enhances cardiac contractility and protects against infarction-induced heart failure. Am. J. Physiol. Heart Circ. Physiol. 293:H3768–71
     [Google Scholar]
/content/journals/10.1146/annurev-physiol-060121-041653
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Adrenergic Regulation of Calcium Channels in the Heart
Annual Review of Physiology 84, 285 (2022); https://doi.org/10.1146/annurev-physiol-060121-041653
/content/journals/10.1146/annurev-physiol-060121-041653
/content/journals/10.1146/annurev-physiol-060121-041653
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