Computational Modeling of Cyclic Nucleotide Signaling Mechanisms in Cardiac Myocytes

  • Claire Y. ZhaoEmail author
Part of the Cardiac and Vascular Biology book series (Abbreviated title: Card. vasc. biol., volume 3)


The balanced signaling between the two cyclic nucleotides (cNs), cAMP and cGMP, in the cN signaling system plays a critical role in regulating cardiac contractility. Many therapeutic agents have been developed to selectively inhibit or stimulate proteins in the cN signaling system in the attempt to manage and treat heart diseases. Nonetheless, it has been challenging to obtain a comprehensive, system-level understanding of the signal transduction mechanisms, in part because of the participation of multiple phosphodiesterases (PDEs) in the common task of cN degradation, the complex interactions between the signaling proteins, and the large number of cN regulated targets in the tightly coupled excitation-contraction (EC) coupling process. Multi-scale, biophysically detailed, and experimentally validated computational models are well suited to dissect the underlying mechanisms in these nonlinear and intertwined reaction networks. By precisely defining and quantifying biochemical reactions involved, data-driven and integrative modeling bridge causal gaps across spatiotemporal scale, from the characteristics of individual molecular components to the collective responses of the entire signaling network. Through predictive modeling and in-depth analysis, these computational models are powerful in providing insights into cellular mechanisms, formulating novel hypothesis, and proposing possible future experiments. This review focuses on the development of mechanistic models, the close interplay between modeling and experimentation, and the identification of opportunities for future modeling research in the cardiac myocyte cN signaling system.


Cyclic nucleotides Phosphodiesterases Signaling network Electrophysiology Compartmentation Heart failure Cardiac myocytes Computational modeling 



This work was supported by Natural Sciences and Engineering Research Council (NSERC) of Canada scholarships, CGS M-377616-2009 and PGSD3-405041-2011, awarded to C.Y.Z.

Compliance with Ethical Standards

Conflict of Interest Statement

The authors declare that they have no conflict of interest.


  1. Abi-Gerges A, Richter W, Lefebvre F, Mateo P, Varin A, Heymes C, Samuel J-L, Lugnier C, Conti M, Fischmeister R (2009) Decreased expression and activity of cAMP phosphodiesterases in cardiac hypertrophy and its impact on β-adrenergic cAMP signals. Circ Res 105(8):784–792PubMedPubMedCentralGoogle Scholar
  2. Abi-Gerges N, Fischmeister R, Méry PF (2001) G protein-mediated inhibitory effect of a nitric oxide donor on the L-type Ca2+ current in rat ventricular myocytes. J Physiol 531(1):117–130PubMedPubMedCentralGoogle Scholar
  3. Ahmad F, Shen W, Vandeput F, Szabo-Fresnais N, Krall J, Degerman E, Goetz F, Klussmann E, Movsesian M, Manganiello V (2015) Regulation of SERCA2 activity by PDE3A in human myocardium: Phosphorylation-dependent interaction of PDE3A1 with SERCA2. Journal of Biological Chemistry:jbc. M115. 638585Google Scholar
  4. Aiba T, Tomaselli GF (2010) Electrical remodeling in the failing heart. Curr Opin Cardiol 25(1):29PubMedPubMedCentralGoogle Scholar
  5. Amanfu RK, Saucerman JJ (2011) Cardiac models in drug discovery and development: a review. 39(5):379–395. doi: 10.1615/CritRevBiomedEng.v39.i5.30 Google Scholar
  6. Antos LLK, Schmidt HH, Hoffmann F, Stasch J-P (2009) cGMP: generators, effectors and therapeutic implications, vol 191. SpringerGoogle Scholar
  7. Aye T-T, Soni S, van Veen TAB, van der Heyden MAG, Cappadona S, Varro A, de Weger RA, de Jonge N, Vos MA, Heck AJR, Scholten A (2012) Reorganized PKA-AKAP associations in the failing human heart. J Mol Cell Cardiol 52(2):511–518. doi: 10.1016/j.yjmcc.2011.06.003 CrossRefPubMedGoogle Scholar
  8. Baillie GS, Huston E, Scotland G, Hodgkin M, Gall I, Peden AH, MacKenzie C, Houslay ES, Currie R, Pettitt TR (2002) TAPAS-1, a novel microdomain within the unique N-terminal region of the PDE4A1 cAMP-specific phosphodiesterase that allows rapid, Ca2+-triggered membrane association with selectivity for interaction with phosphatidic acid. J Biol Chem 277(31):28298–28309PubMedGoogle Scholar
  9. Balijepalli RC, Foell JD, Hall DD, Hell JW, Kamp TJ (2006) Localization of cardiac L-type Ca2+ channels to a caveolar macromolecular signaling complex is required for β2-adrenergic regulation. Proc Natl Acad Sci 103(19):7500–7505PubMedGoogle Scholar
  10. Balligand J-L (1999) Regulation of cardiac β-adrenergic response by nitric oxide. Cardiovasc Res 43(3):607–620. doi: 10.1016/s0008-6363(99)00163-7 CrossRefPubMedGoogle Scholar
  11. Balligand J-L, Kelly RA, Marsden PA, Smith TW, Michel T (1993) Control of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc Natl Acad Sci 90(1):347–351PubMedGoogle Scholar
  12. Batchelor AM, Bartus K, Reynell C, Constantinou S, Halvey EJ, Held KF, Dostmann WR, Vernon J, Garthwaite J (2010) Exquisite sensitivity to subsecond, picomolar nitric oxide transients conferred on cells by guanylyl cyclase-coupled receptors. Proc Natl Acad Sci 107(51):22060–22065. doi: 10.1073/pnas.1013147107 CrossRefPubMedGoogle Scholar
  13. Beavo J, Hardman JG, Sutherland EW (1971) Stimulation of adenosine 3', 5'-monophosphate hydrolysis by guanosine 3', 5'-monophosphate. J Biol Chem 246(12):3841–3846PubMedGoogle Scholar
  14. Beavo JA (1995) Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 75(4):725–748PubMedGoogle Scholar
  15. Beavo JA, Brunton LL (2002) Cyclic nucleotide research -- still expanding after half a century. Nat Rev Mol Cell Biol 3(9):710–718PubMedGoogle Scholar
  16. Beca S, Helli PB, Simpson JA, Zhao D, Farman GP, Jones PP, Tian X, Wilson LS, Ahmad F, Chen SRW, Movsesian MA, Manganiello V, Maurice DH, Conti M, Backx PH (2011) Phosphodiesterase 4D regulates baseline sarcoplasmic reticulum Ca2+ release and cardiac contractility, independently of L-type Ca2+ current. Circ Res 109(9):1024–1030. doi: 10.1161/circresaha.111.250464 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Bellamy TC, Wood J, Goodwin DA, Garthwaite J (2000) Rapid desensitization of the nitric oxide receptor, soluble guanylyl cyclase, underlies diversity of cellular cGMP responses. Proc Natl Acad Sci 97(6):2928–2933PubMedGoogle Scholar
  18. Bender AT, Beavo JA (2006) Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58(3):488–520PubMedGoogle Scholar
  19. Benitah J-P, Alvarez JL, Gómez AM (2010) L-type Ca 2+ current in ventricular cardiomyocytes. J Mol Cell Cardiol 48(1):26–36PubMedGoogle Scholar
  20. Bers DM (2001) Excitation contraction coupling and cardiac contractile force, 2nd edn. Kluwer Academic Publishers, DordrechtGoogle Scholar
  21. Bers DM (2002) Cardiac excitation–contraction coupling. Nature 415(6868):198–205Google Scholar
  22. Bers DM (2006) Cardiac ryanodine receptor phosphorylation: target sites and functional consequences. Biochem J 396(1). doi: 10.1042/bj20060377
  23. Bethke T, Meyer W, Schmitz W, Scholz H, Stein B, Thomas K, Wenzlaff H (1992) Phosphodiesterase inhibition in ventricular cardiomyocytes from Guinea-pig hearts. Br J Pharmacol 107(1):127–133PubMedPubMedCentralGoogle Scholar
  24. Bode DC, Kanter JR, Brunton LL (1991) Cellular distribution of phosphodiesterase isoforms in rat cardiac tissue. Circ Res 68(4):1070–1079PubMedGoogle Scholar
  25. Boerrigter G, Lapp H, Burnett JC (2009) Modulation of cGMP in heart failure: a new therapeutic paradigm. In: cGMP: generators, effectors and therapeutic implications. Springer. pp 485–506Google Scholar
  26. Böhm M, Gierschik P, Jakobs K-H, Pieske B, Schnabel P, Ungerer M, Erdmann E (1990) Increase of Gi alpha in human hearts with dilated but not ischemic cardiomyopathy. Circulation 82(4):1249–1265PubMedGoogle Scholar
  27. Bondarenko VE (2014) A compartmentalized mathematical model of the β 1-adrenergic signaling system in mouse ventricular myocytes. PLoS One 9(2):e89113PubMedPubMedCentralGoogle Scholar
  28. Bristow M, Hershberger R, Port JD, Minobe W, Rasmussen R (1989) Beta 1-and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. Mol Pharmacol 35(3):295–303PubMedGoogle Scholar
  29. Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB (1982) Decreased catecholamine sensitivity and β-adrenergic-receptor density in failing human hearts. N Engl J Med 307(4):205–211Google Scholar
  30. Bristow MR, Ginsburg R, Umans V, Fowler M, Minobe W, Rasmussen R, Zera P, Menlove R, Shah P, Jamieson S (1986) Beta 1-and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. Circ Res 59(3):297–309Google Scholar
  31. Brunton LL, Hayes JS, Mayer SE (1979) Hormonally specific phosphorylation of cardiac troponin I and activation of glycogen phosphorylase.PubMedGoogle Scholar
  32. Buerk DG (2001) Can we model nitric oxide biotransport? A survey of mathematical models for a simple diatomic molecule with surprisingly complex biological activities. Annu Rev Biomed Eng 3(1):109–143PubMedGoogle Scholar
  33. Calaghan S, Kozera L, White E (2008) Compartmentalisation of cAMP-dependent signalling by caveolae in the adult cardiac myocyte. J Mol Cell Cardiol 45(1):88–92. doi: 10.1016/j.yjmcc.2008.04.004 CrossRefPubMedGoogle Scholar
  34. Castro LRV, Schittl J, Fischmeister R (2010) Feedback control through cGMP-dependent protein kinase contributes to differential regulation and compartmentation of cGMP in rat cardiac myocytes. Circ Res 107(10):1232–1240. doi: 10.1161/circresaha.110.226712 CrossRefPubMedGoogle Scholar
  35. Castro LRV, Verde I, Cooper DMF, Fischmeister R (2006) Cyclic guanosine monophosphate compartmentation in rat cardiac myocytes. Circulation 113(18):2221–2228. doi: 10.1161/circulationaha.105.599241 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Catterall WA (2000) Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol 16(1):521–555PubMedGoogle Scholar
  37. Cawley SM, Sawyer CL, Brunelle KF, van der Vliet A, Dostmann WR (2007) Nitric oxide-evoked transient kinetics of cyclic GMP in vascular smooth muscle cells. Cell Signal 19(5):1023–1033. doi: 10.1016/j.cellsig.2006.11.012 CrossRefPubMedGoogle Scholar
  38. Champion HC, Skaf MW, Hare JM (2004) Role of nitric oxide in the pathophysiology of heart failure. In: The role of nitric oxide in heart failure. Springer, pp 81–92Google Scholar
  39. Chen K, Popel AS (2006) Theoretical analysis of biochemical pathways of nitric oxide release from vascular endothelial cells. Free Radic Biol Med 41(4):668–680PubMedGoogle Scholar
  40. Chen K, Popel AS (2007) Vascular and perivascular nitric oxide release and transport: biochemical pathways of neuronal nitric oxide synthase (NOS1) and endothelial nitric oxide synthase (NOS3). Free Radic Biol Med 42(6):811–822PubMedGoogle Scholar
  41. Chen L, Kass RS (2011) A-kinase anchoring protein 9 and I(Ks) channel regulation. J Cardiovasc Pharmacol 58(5):459–413. doi: 10.1097/FJC.0b013e318232c80c CrossRefPubMedPubMedCentralGoogle Scholar
  42. Chen X, Piacentino V, Furukawa S, Goldman B, Margulies KB, Houser SR (2002) L-type Ca2+ channel density and regulation are altered in failing human ventricular myocytes and recover after support with mechanical assist devices. Circ Res 91(6):517–524. doi: 10.1161/01.res.0000033988.13062.7c CrossRefPubMedGoogle Scholar
  43. Christ T, Galindo-Tovar A, Thoms M, Ravens U, Kaumann AJ (2009) Inotropy and L-type Ca2+ current, activated by β1- and β2-adrenoceptors, are differently controlled by phosphodiesterases 3 and 4 in rat heart. Br J Pharmacol 156(1):62–83. doi: 10.1111/j.1476-5381.2008.00015.x CrossRefPubMedPubMedCentralGoogle Scholar
  44. Cohen P (2002) Protein kinases—the major drug targets of the twenty-first century? Nat Rev Drug Discov 1(4):309–315PubMedGoogle Scholar
  45. Colyer J (1998) Phosphorylation states of Phospholamban. Ann N Y Acad Sci 853(1):79–91PubMedGoogle Scholar
  46. Conti M, Beavo J (2007) Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 76:481–511Google Scholar
  47. Conti M, Mika D, Richter W (2014) Cyclic AMP compartments and signaling specificity: role of cyclic nucleotide phosphodiesterases. J Gen Physiol 143(1):29–38. doi: 10.1085/jgp.201311083 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Corbin JD, Turko IV, Beasley A, Francis SH (2000) Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. Eur J Biochem 267(9):2760–2767PubMedGoogle Scholar
  49. Damy T, Ratajczak P, Shah AM, Camors E, Marty I, Hasenfuss G, Marotte F, Samuel J-L, Heymes C (2004) Increased neuronal nitric oxide synthase-derived NO production in the failing human heart. Lancet 363(9418):1365–1367Google Scholar
  50. Degerman E, Belfrage P, Manganiello VC (1997) Structure, localization, and regulation of cGMP-inhibited phosphodiesterase (PDE3). J Biol Chem 272(11):6823–6826. doi: 10.1074/jbc.272.11.6823 CrossRefPubMedGoogle Scholar
  51. Despa S, Bossuyt J, Han F, Ginsburg KS, Jia L-G, Kutchai H, Tucker AL, Bers DM (2005) Phospholemman-phosphorylation mediates the β-adrenergic effects on Na/K pump function in cardiac myocytes. Circ Res 97(3):252–259. doi: 10.1161/01.RES.0000176532.97731.e5 CrossRefPubMedGoogle Scholar
  52. Despa S, Tucker AL, Bers DM (2008) Phospholemman-mediated activation of Na/K-ATPase limits [Na]i and inotropic state during β-adrenergic stimulation in mouse ventricular myocytes. Circulation 117(14):1849–1855. doi: 10.1161/circulationaha.107.754051 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Di Benedetto G, Zoccarato A, Lissandron V, Terrin A, Li X, Houslay MD, Baillie GS, Zaccolo M (2008) Protein kinase a type I and type II define distinct intracellular signaling compartments. Circ Res 103(8):836–844. doi: 10.1161/circresaha.108.174813 CrossRefPubMedGoogle Scholar
  54. Ding B, J-i A, Wei H, Huang Q, Walsh RA, Molina CA, Zhao A, Sadoshima J, Blaxall BC, Berk BC, Yan C (2005a) Functional role of phosphodiesterase 3 in cardiomyocyte apoptosis: implication in heart failure. Circulation 111(19):2469–2476. doi: 10.1161/01.cir.0000165128.39715.87 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Ding B, J-i A, Wei H, Xu H, Che W, Aizawa T, Liu W, Molina CA, Sadoshima J, Blaxall BC, Berk BC, Yan C (2005b) A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis. Proc Natl Acad Sci U S A 102(41):14771–14776. doi: 10.1073/pnas.0506489102 CrossRefPubMedPubMedCentralGoogle Scholar
  56. Dodge KL, Khouangsathiene S, Kapiloff MS, Mouton R, Hill EV, Houslay MD, Langeberg LK, Scott JD (2001) mAKAP assembles a protein kinase a/PDE4 phosphodiesterase cAMP signaling module. EMBO J 20(8):1921–1930PubMedPubMedCentralGoogle Scholar
  57. Dzimiri N (1999) Regulation of β-adrenoceptor signaling in cardiac function and disease. Pharmacol Rev 51(3):465–502PubMedGoogle Scholar
  58. El-Armouche A, Pamminger T, Ditz D, Zolk O, Eschenhagen T (2004) Decreased protein and phosphorylation level of the protein phosphatase inhibitor-1 in failing human hearts. Cardiovasc Res 61(1):87–93. doi: 10.1016/j.cardiores.2003.11.005 CrossRefPubMedGoogle Scholar
  59. Espinasse I, Iourgenko V, Richer C, Heimburger M, Defer N, Bourin M-C, Samson F, Pussard E, Giudicelli J-F, Michel J-B, Hanoune J, Mercadier J-J (1999) Decreased type VI adenylyl cyclase mRNA concentration and Mg2+−dependent adenylyl cyclase activities and unchanged type V adenylyl cyclase mRNA concentration and Mn2+−dependent adenylyl cyclase activities in the left ventricle of rats with myocardial inf…. Cardiovascular Research 42 (1):87–98. doi: 10.1016/s0008-6363(98)00283-1 PubMedGoogle Scholar
  60. Feldman DS, Carnes CA, Abraham WT, Bristow MR (2005) Mechanisms of disease: [beta]-adrenergic receptors[mdash]alterations in signal transduction and pharmacogenomics in heart failure. Nat Clin Pract Cardiovasc Med 2(9):475–483PubMedGoogle Scholar
  61. Fiedler B, Lohmann SM, Smolenski A, Linnemüller S, Pieske B, Schröder F, Molkentin JD, Drexler H, Wollert KC (2002) Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes. Proc Natl Acad Sci 99(17):11363–11368PubMedGoogle Scholar
  62. Fink M, Niederer SA, Cherry EM, Fenton FH, Koivumäki JT, Seemann G, Thul R, Zhang H, Sachse FB, Beard D, Crampin EJ, Smith NP (2011) Cardiac cell modelling: observations from the heart of the cardiac physiome project. Prog Biophys Mol Biol 104(1–3):2–21. doi: 10.1016/j.pbiomolbio.2010.03.002 CrossRefPubMedGoogle Scholar
  63. Fischmeister R, Castro LR, Abi-Gerges A, Rochais F, Jurevičius J, Leroy J, Vandecasteele G (2006) Compartmentation of cyclic nucleotide signaling in the heart the role of cyclic nucleotide phosphodiesterases. Circ Res 99(8):816–828PubMedGoogle Scholar
  64. Francis SH, Blount MA, Corbin JD (2011) Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol Rev 91(2):651–690Google Scholar
  65. Francis SH, Busch JL, Corbin JD (2010) cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev 62(3):525–563. doi: 10.1124/pr.110.002907 CrossRefPubMedPubMedCentralGoogle Scholar
  66. Francis SH, Corbin JD, Bischoff E (2009) Cyclic GMP-hydrolyzing phosphodiesterases. In: cGMP: generators, effectors and therapeutic implications. Springer, pp 367–408Google Scholar
  67. Graves JD, Krebs EG (1999) Protein phosphorylation and signal transduction. Pharmacol Ther 82(2–3):111–121. doi: 10.1016/S0163-7258(98)00056-4 CrossRefPubMedGoogle Scholar
  68. Grushin K, Nenov M, Dynnik V, Semushina S, Pakhomova I, Murashev A, Kokoz YM (2008) Role of the NO-cGMP cascade in regulation of L-type Ca2+ currents in isolated cardiomyocytes. Biochem (Moscow) Suppl Ser A Membr Cell Biol 2(3):243–252Google Scholar
  69. Guazzi M (2008) Clinical use of phosphodiesterase-5 inhibitors in chronic heart failure. Circ Heart Fail 1(4):272–280. doi: 10.1161/circheartfailure.108.802116 CrossRefPubMedGoogle Scholar
  70. Guo D, Young L, Patel C, Jiao Z, Wu Y, Liu T, Kowey PR, Yan G-X (2008) Calcium-activated chloride current contributes to action potential alternations in left ventricular hypertrophy rabbit. Am J Physiol Heart Circ Physiol 295(1):H97–H104. doi: 10.1152/ajpheart.01032.2007 CrossRefPubMedGoogle Scholar
  71. Gupta RC, Neumann J, Watanabe AM, Lesch M, Sabbah HN (1996) Evidence for presence and hormonal regulation of protein phosphatase inhibitor-1 in ventricular cardiomyocyte. Am J Physiol Heart Circ Physiol 270(4):H1159–H1164Google Scholar
  72. Hall CN, Garthwaite J (2009) What is the real physiological NO concentration in vivo? Nitric Oxide 21(2):92–103. doi: 10.1016/j.niox.2009.07.002 CrossRefPubMedPubMedCentralGoogle Scholar
  73. Hambleton R, Krall J, Tikishvili E, Honeggar M, Ahmad F, Manganiello VC, Movsesian MA (2005) Isoforms of cyclic nucleotide phosphodiesterase PDE3 and their contribution to cAMP hydrolytic activity in subcellular fractions of human myocardium. J Biol Chem 280(47):39168–39174. doi: 10.1074/jbc.M506760200 CrossRefPubMedGoogle Scholar
  74. Hammer KP, Ljubojevic S, Ripplinger CM, Pieske BM, Bers DM (2015) Cardiac myocyte alternans in intact heart: influence of cell–cell coupling and β-adrenergic stimulation. J Mol Cell Cardiol 84:1–9PubMedPubMedCentralGoogle Scholar
  75. Hammond J, Balligand J-L (2012) Nitric oxide synthase and cyclic GMP signaling in cardiac myocytes: from contractility to remodeling. J Mol Cell Cardiol 52(2):330–340. doi: 10.1016/j.yjmcc.2011.07.029 CrossRefPubMedGoogle Scholar
  76. Harmati G, Banyasz T, Barandi L, Szentandrássy N, Horvath B, Szabo G, Szentmiklósi J, Szenasi G, Nanasi P, Magyar J (2011) Effects of β-adrenoceptor stimulation on delayed rectifier K+ currents in canine ventricular cardiomyocytes. Br J Pharmacol 162(4):890–896PubMedPubMedCentralGoogle Scholar
  77. Harvey RD, Hell JW (2013) Ca< sub> V 1.2 signaling complexes in the heart. J Mol Cell Cardiol 58:143–152Google Scholar
  78. Hayes JS, Brunton LL, Brown JH, Reese JB, Mayer SE (1979) Hormonally specific expression of cardiac protein kinase activity. Proc Natl Acad Sci 76(4):1570–1574PubMedGoogle Scholar
  79. He R, Komas N, Ekholm D, Murata T, Taira M, Hockman S, Degerman E, Manganiello VC (1998) Expression and characterization of deletion recombinants of two cGMP-inhibited cyclic nucleotide phosphodiesterases (PDE-3). Cell Biochem Biophys 29(1–2):89–111PubMedGoogle Scholar
  80. Heijman J, Volders PG, Westra RL, Rudy Y (2011) Local control of β-adrenergic stimulation: effects on ventricular myocyte electrophysiology and Ca2+-transient. J Mol Cell Cardiol 50(5):863–871PubMedPubMedCentralGoogle Scholar
  81. Heinzen EL, Pollack GM (2003) Pharmacokinetics and pharmacodynamics of L-arginine in rats: a model of stimulated neuronal nitric oxide synthesis. Brain Res 989(1):67–75PubMedGoogle Scholar
  82. Held KF, Dostmann WR (2012) Sub-nanomolar sensitivity of nitric oxide mediated regulation of cGMP and vasomotor reactivity in vascular smooth muscle. Front Pharmacol:3. doi: 10.3389/fphar.2012.00130
  83. Herget S, Lohse MJ, Nikolaev VO (2008) Real-time monitoring of phosphodiesterase inhibition in intact cells. Cell Signal 20(8):1423–1431. doi: 10.1016/j.cellsig.2008.03.011 CrossRefPubMedGoogle Scholar
  84. Hofmann F, Bernhard D, Lukowski R, Weinmeister P (2009) cGMP regulated protein kinases (cGK). In: Schmidt HHW, Hofmann F, Stasch J-P (eds) cGMP: generators, effectors and therapeutic implications, Handbook of experimental pharmacology, vol 191. Springer, Berlin, pp 137–162. doi: 10.1007/978-3-540-68964-5_8 CrossRefGoogle Scholar
  85. Hohl CM, Li Q (1991) Compartmentation of cAMP in adult canine ventricular myocytes. Relation to single-cell free Ca2+ transients. Circ Res 69(5):1369–1379PubMedGoogle Scholar
  86. Houslay MD, Adams DR (2003) PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J 370(1):1–18. doi: 10.1042/bj20021698 CrossRefPubMedPubMedCentralGoogle Scholar
  87. Huggins JP, Cook EA, Piggott JR, Mattinsley T, England P (1989) Phospholamban is a good substrate for cyclic GMP-dependent protein kinase in vitro, but not in intact cardiac or smooth muscle. Biochem J 260(3):829–835PubMedPubMedCentralGoogle Scholar
  88. Hwang TC, Horie M, Gadsby DC (1993) Functionally distinct phospho-forms underlie incremental activation of protein kinase-regulated Cl- conductance in mammalian heart. J Gen Physiol 101(5):629–650. doi: 10.1085/jgp.101.5.629 CrossRefPubMedGoogle Scholar
  89. Iancu RV, Jones SW, Harvey RD (2007) Compartmentation of cAMP signaling in cardiac myocytes: a computational study. Biophys J 92(9):3317–3331PubMedPubMedCentralGoogle Scholar
  90. Iancu RV, Ramamurthy G, Warrier S, Nikolaev VO, Lohse MJ, Jones SW, Harvey RD (2008) Cytoplasmic cAMP concentrations in intact cardiac myocytes. Am J Phys Cell Phys 295(2):C414Google Scholar
  91. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci 84(24):9265–9269PubMedGoogle Scholar
  92. Imai Y, Jiang B, Pappano AJ (2001) Mechanism for muscarinic inhibition of ICa (L) is determined by the path for elevating cyclic AMP in cardiac myocytes. Cardiovasc Res 51(2):331–343PubMedGoogle Scholar
  93. Ishikawa Y, Sorota S, Kiuchi K, Shannon RP, Komamura K, Katsushika S, Vatner DE, Vatner SF, Homcy CJ (1994) Downregulation of adenylylcyclase types V and VI mRNA levels in pacing-induced heart failure in dogs. J Clin Investig 93(5):2224–2229PubMedGoogle Scholar
  94. Jäger R, Schwede F, Genieser H-G, Koesling D, Russwurm M (2010) Activation of PDE2 and PDE5 by specific GAF ligands: delayed activation of PDE5. Br J Pharmacol 161(7):1645–1660. doi: 10.1111/j.1476-5381.2010.00977.x CrossRefPubMedPubMedCentralGoogle Scholar
  95. Janse MJ (2004) Electrophysiological changes in heart failure and their relationship to arrhythmogenesis. Cardiovasc Res 61(2):208–217. doi: 10.1016/j.cardiores.2003.11.018 CrossRefPubMedGoogle Scholar
  96. Jiang L, Gawler D, Hodson N, Milligan C, Pearson H, Porter V, Wray D (2000) Regulation of cloned cardiac L-type calcium channels by cGMP-dependent protein kinase. J Biol Chem 275(9):6135–6143PubMedGoogle Scholar
  97. Josephson IR, Guia A, Lakatta EG, Lederer WJ, Stern MD (2010) Ca2+-dependent components of inactivation of unitary cardiac L-type Ca2+ channels. J Physiol 588(1):213–223PubMedGoogle Scholar
  98. Kameyama M, Hofmann F, Trautwein W (1985) On the mechanism of β-adrenergic regulation of the Ca channel in the Guinea-pig heart. Pflugers Arch 405(3):285–293PubMedGoogle Scholar
  99. Kapela A, Bezerianos A, Tsoukias NM (2008) A mathematical model of Ca 2+ dynamics in rat mesenteric smooth muscle cell: agonist and NO stimulation. J Theor Biol 253(2):238–260PubMedGoogle Scholar
  100. Kar S, Kavdia M (2011) Modeling of biopterin-dependent pathways of eNOS for nitric oxide and superoxide production. Free Radic Biol Med 51(7):1411–1427PubMedPubMedCentralGoogle Scholar
  101. Kass DA (2012) Heart failure: a PKGarious balancing act. Circulation:CIRCULATIONAHA 112:124909Google Scholar
  102. Kass DA, Champion HC, Beavo JA (2007a) Phosphodiesterase type 5 expanding roles in cardiovascular regulation. Circ Res 101(11):1084–1095PubMedGoogle Scholar
  103. Kass DA, Takimoto E, Nagayama T, Champion HC (2007b) Phosphodiesterase regulation of nitric oxide signaling. Cardiovasc Res 75(2):303–314PubMedGoogle Scholar
  104. Katsube Y, Yokoshiki H, Nguyen L, Sperelakis N (1996) Differences in isoproterenol stimulation of Ca2+ current of rat ventricular myocytes in neonatal compared to adult. Eur J Pharmacol 317(2):391–400PubMedGoogle Scholar
  105. Katz A (2011) Physiology of the heart. Wolters Kluwer Health,Google Scholar
  106. Klein G, Drexler H, Schröder F (2000) Protein kinase G reverses all isoproterenol induced changes of cardiac single L-type calcium channel gating. Cardiovasc Res 48(3):367–374PubMedGoogle Scholar
  107. Knight W, Yan C (2012) Cardiac cyclic nucleotide phosphodiesterases: function, regulation, and therapeutic prospects. Hormone and metabolic research= Hormon-und Stoffwechselforschung= Hormones et metabolisme 44 (10):766Google Scholar
  108. Koch WJ, Rockman HA, Samama P, Hamilton R, Bond RA, Milano CA, Lefkowitz RJ (1995) Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor. Science 268(5215):1350–1353PubMedGoogle Scholar
  109. Koitabashi N, Aiba T, Hesketh GG, Rowell J, Zhang M, Takimoto E, Tomaselli GF, Kass DA (2010) Cyclic GMP/PKG-dependent inhibition of TRPC6 channel activity and expression negatively regulates cardiomyocyte NFAT activation: novel mechanism of cardiac stress modulation by PDE5 inhibition. J Mol Cell Cardiol 48(4):713–724Google Scholar
  110. Komas N, Le Bec A, Stoclet J-C, Lugnier C (1991) Cardiac cGMP-stimulated cyclic nucleotide phosphodiesterases: effects of cGMP analogues and drugs. Eur J Pharmacol Mol Pharmacol 206(1):5–13Google Scholar
  111. Kostic M, Erdogan S, Rena G, Borchert G, Hoch B, Bartel S, Scotland G, Huston E, Houslay M, Krause E-G (1997) Altered expression of PDE1 and PDE4 cyclic nucleotide phosphodiesterase isoforms in 7-oxo-prostacyclin-preconditioned rat heart. J Mol Cell Cardiol 29(11):3135–3146PubMedGoogle Scholar
  112. Kots AY, Martin E, Sharina IG, Murad F (2009) A short history of cGMP, guanylyl cyclases, and cGMP-dependent protein kinases. In: cGMP: generators, effectors and therapeutic implications. Springer, pp 1–14Google Scholar
  113. Krüger M, Kötter S, Grützner A, Lang P, Andresen C, Redfield MM, Butt E, dos Remedios CG, Linke WA (2009) Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the Titin Springs. Circ Res 104(1):87–94. doi: 10.1161/circresaha.108.184408 CrossRefPubMedGoogle Scholar
  114. Kuhn M (2003) Structure, regulation, and function of mammalian membrane guanylyl cyclase receptors, with a focus on guanylyl cyclase-a. Circ Res 93(8):700–709PubMedGoogle Scholar
  115. Kuhn M (2004) Molecular physiology of natriuretic peptide signalling. Basic Res Cardiol 99(2):76–82. doi: 10.1007/s00395-004-0460-0 CrossRefPubMedGoogle Scholar
  116. Kuhn M (2015) Cardiology: a big-hearted molecule. Nature 519(7544):416–417. doi: 10.1038/nature14373 CrossRefPubMedGoogle Scholar
  117. Kuhn M, Holtwick R, Baba H, Perriard J, Schmitz W, Ehler E (2002) Progressive cardiac hypertrophy and dysfunction in atrial natriuretic peptide receptor (GC-A) deficient mice. Heart 87(4):368–374PubMedPubMedCentralGoogle Scholar
  118. Kumar R, Namiki T, Joyner RW (1997) Effects of cGMP on L-type calcium current of adult and newborn rabbit ventricular cells. Cardiovasc Res 33(3):573–582PubMedGoogle Scholar
  119. Kurokawa J, Bankston JR, Kaihawa A, Chen L, Furukawa T, Kass RS (2009) KCNE variants reveal a critical role of the beta subunit carboxyl terminus in PKA-dependent regulation of the IKs potassium channel. Channels 3(1):16–24. doi: 10.4161/chan.3.1.7387 CrossRefPubMedGoogle Scholar
  120. Kuznetsov V, Pak E, Robinson RB, Steinberg SF (1995) β2-adrenergic receptor actions in neonatal and adult rat ventricular myocytes. Circ Res 76(1):40–52. doi: 10.1161/01.res.76.1.40 CrossRefPubMedGoogle Scholar
  121. Kuzumoto M, Takeuchi A, Nakai H, Oka C, Noma A, Matsuoka S (2008) Simulation analysis of intracellular Na+ and Cl− homeostasis during β1-adrenergic stimulation of cardiac myocyte. Prog Biophys Mol Biol 96(1–3):171–186. doi: 10.1016/j.pbiomolbio.2007.07.005 CrossRefPubMedGoogle Scholar
  122. Laflamme MA, Becker PL (1999) Gs and adenylyl cyclase in transverse tubules of heart: implications for cAMP-dependent signaling. Am J Physiol Heart Circ Physiol 277(5):H1841–H1848Google Scholar
  123. Lamba MS, Abraham MWT (2000) Alterations in adrenergic receptor signaling in heart failure. Heart Fail Rev 5(1):7–16PubMedGoogle Scholar
  124. Lee DI, Kass DA (2012) Phosphodiesterases and cyclic GMP regulation in heart muscle. Physiology 27(4):248–258. doi: 10.1152/physiol.00011.2012 CrossRefPubMedGoogle Scholar
  125. Lee DI, Vahebi S, Tocchetti CG, Barouch LA, Solaro RJ, Takimoto E, Kass DA (2010) PDE5A suppression of acute β-adrenergic activation requires modulation of myocyte beta-3 signaling coupled to PKG-mediated troponin I phosphorylation. Basic Res Cardiol 105(3):337–347. doi: 10.1007/s00395-010-0084-5 CrossRefPubMedPubMedCentralGoogle Scholar
  126. Lee DI, Zhu G, Sasaki T, Cho G-S, Hamdani N, Holewinski R, Jo S-H, Danner T, Zhang M, Rainer PP, Bedja D, Kirk JA, Ranek MJ, Dostmann WR, Kwon C, Margulies KB, Van Eyk JE, Paulus WJ, Takimoto E, Kass DA (2015) Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature 519 (7544):472–476. doi: 10.1038/nature14332. - supplementary-informationPubMedPubMedCentralGoogle Scholar
  127. Lehnart SE, Wehrens XH, Reiken S, Warrier S, Belevych AE, Harvey RD, Richter W, Jin S-LC, Conti M, Marks AR (2005) Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. Cell 123(1):25–35PubMedPubMedCentralGoogle Scholar
  128. Leroy J, Abi-Gerges A, Nikolaev VO, Richter W, Lechêne P, Mazet J-L, Conti M, Fischmeister R, Vandecasteele G (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(9):1091–1100PubMedGoogle Scholar
  129. Levi RC, Alloatti G, Fischmeister R (1989) Cyclic GMP regulates the Ca-channel current in Guinea pig ventricular myocytes. Pflügers Archiv-Eur J Physiol 413(6):685–687Google Scholar
  130. Levi RC, Alloatti G, Penna C, Gallo MP (1994) Guanylate-cyclase-mediated inhibition of cardiac I Ca by carbachol and sodium nitroprusside. Pflugers Arch 426(5):419–426PubMedGoogle Scholar
  131. 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(3):H769–H779PubMedGoogle Scholar
  132. Lohse MJ, Engelhardt S, Eschenhagen T (2003) What is the role of β-adrenergic signaling in heart failure? Circ Res 93(10):896–906Google Scholar
  133. Lohse MJ, Nikolaev VO, Hein P, Hoffmann C, Vilardaga J-P, Bünemann M (2008) Optical techniques to analyze real-time activation and signaling of G-protein-coupled receptors. Trends Pharmacol Sci 29(3):159–165. doi: 10.1016/ CrossRefPubMedGoogle Scholar
  134. Loyer X, Heymes C, Samuel JL (2008) Constitutive nitric oxide synthases in the heart from hypertrophy to failure. Clin Exp Pharmacol Physiol 35(4):483–488PubMedGoogle Scholar
  135. Lu Z, Xu X, Hu X, Lee S, Traverse JH, Zhu G, Fassett J, Tao Y, Zhang P, dos Remedios C (2010) Oxidative stress regulates left ventricular PDE5 expression in the failing heart. Circulation 121(13):1474–1483PubMedPubMedCentralGoogle Scholar
  136. Lugnier C (2006) Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther 109(3):366–398PubMedGoogle Scholar
  137. MacKenzie SJ, Baillie GS, McPhee I, MacKenzie C, Seamons R, McSorley T, Millen J, Beard MB, Heeke G, Houslay MD (2002) Long PDE4 cAMP specific phosphodiesterases are activated by protein kinase A-mediated phosphorylation of a single serine residue in upstream conserved region 1 (UCR1). Br J Pharmacol 136(3):421–433PubMedPubMedCentralGoogle Scholar
  138. Marín-García J (2010) Cyclic nucleotides signaling (second messengers) and control of myocardial function: effects of heart failure. In: heart failure. contemporary cardiology. Humana Press, pp 161–169. doi: 10.1007/978-1-60761-147-9_8 Google Scholar
  139. Marston SB, de Tombe PP (2008) Point/counterpoint troponin phosphorylation and myofilament Ca(2+)-sensitivity in heart failure: increased or decreased? J Mol Cell Cardiol 45(5):603–607. doi: 10.1016/j.yjmcc.2008.07.004 CrossRefPubMedPubMedCentralGoogle Scholar
  140. Martinez SE, Wu AY, Glavas NA, Tang X-B, Turley S, Hol WGJ, Beavo JA (2002) The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding. Proc Natl Acad Sci 99(20):13260–13265. doi: 10.1073/pnas.192374899 CrossRefPubMedGoogle Scholar
  141. Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR (2000) PKA phosphorylation dissociates FKBP12.6 from the calcium Release Channel (ryanodine receptor): defective regulation in failing hearts. Cell 101(4):365–376. doi: 10.1016/S0092-8674(00)80847-8 CrossRefPubMedGoogle Scholar
  142. Marzo KP, Frey MJ, Wilson JR, Liang BT, Manning DR, Lanoce V, Molinoff PB (1991) Beta-adrenergic receptor-G protein-adenylate cyclase complex in experimental canine congestive heart failure produced by rapid ventricular pacing. Circ Res 69(6):1546–1556PubMedGoogle Scholar
  143. Massion PB, Pelat M, Belge C, Balligand J-L (2005) Regulation of the mammalian heart function by nitric oxide. Comp Biochem Physiol A Mol Integr Physiol 142(2):144–150PubMedGoogle Scholar
  144. Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello VC (2014) Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov 13(4):290–314PubMedPubMedCentralGoogle Scholar
  145. McKie PM, Burnett JC Jr (2005) B-type natriuretic peptide as a biomarker beyond heart failure: speculations and opportunities. Mayo Clin Proc 80(8):1029–1036. doi: 10.4065/80.8.1029 CrossRefPubMedGoogle Scholar
  146. Mehel H, Emons J, Vettel C, Wittköpper K, Seppelt D, Dewenter M, Lutz S, Sossalla S, Maier LS, Lechêne P (2013) Phosphodiesterase-2 is up-regulated in human failing hearts and blunts β-adrenergic responses in cardiomyocytes. J Am Coll Cardiol 62(17):1596–1606Google Scholar
  147. Menniti FS, Faraci WS, Schmidt CJ (2006) Phosphodiesterases in the CNS: targets for drug development. Nat Rev Drug Discov 5(8):660–670PubMedGoogle Scholar
  148. Méry PF, Lohmann SM, Walter U, Fischmeister R (1991) Ca2+ current is regulated by cyclic GMP-dependent protein kinase in mammalian cardiac myocytes. Proc Natl Acad Sci 88(4):1197–1201. doi: 10.1073/pnas.88.4.1197 CrossRefPubMedGoogle Scholar
  149. Méry PF, Pavoine C, Pecker F, Fischmeister R (1995) Erythro-9-(2-hydroxy-3-nonyl)adenine inhibits cyclic GMP-stimulated phosphodiesterase in isolated cardiac myocytes. Mol Pharmacol 48(1):121–130PubMedGoogle Scholar
  150. Mika D, Leroy J, Vandecasteele G, Fischmeister R (2012) PDEs create local domains of cAMP signaling. J Mol Cell Cardiol 52(2):323–329PubMedGoogle Scholar
  151. Mika D, Richter W, Westenbroek RE, Catterall WA, Conti M (2014) PDE4B mediates local feedback regulation of β1-adrenergic cAMP signaling in a sarcolemmal compartment of cardiac myocytes. J Cell Sci 127(5):1033–1042. doi: 10.1242/jcs.140251 CrossRefPubMedPubMedCentralGoogle Scholar
  152. Miller CL, Oikawa M, Cai Y, Wojtovich AP, Nagel DJ, Xu X, Xu H, Florio V, Rybalkin SD, Beavo JA, Chen Y-F, Li J-D, Blaxall BC, J-i A, Yan C (2009) Role of Ca2+/calmodulin-stimulated cyclic nucleotide phosphodiesterase 1 in mediating cardiomyocyte hypertrophy. Circ Res 105(10):956–964. doi: 10.1161/circresaha.109.198515 CrossRefPubMedPubMedCentralGoogle Scholar
  153. Miller CL, Yan C (2010) Targeting cyclic nucleotide phosphodiesterase in the heart: therapeutic implications. J Cardiovasc Transl Res 3(5):507–515PubMedPubMedCentralGoogle Scholar
  154. Mo E, Amin H, Bianco IH, Garthwaite J (2004) Kinetics of a cellular nitric oxide/cGMP/phosphodiesterase-5 pathway. J Biol Chem 279(25):26149–26158PubMedGoogle Scholar
  155. Moalem J, Weiss HR, Davidov T, Rodriguez R, Molino B, Lazar MJ, Scholz PM (2006) Heart failure reduces both the effects and interaction between cyclic GMP and cyclic AMP. J Surg Res 134(2):300–306. doi: 10.1016/j.jss.2006.01.015 CrossRefPubMedGoogle Scholar
  156. Molina CE, Leroy J, Richter W, Xie M, Scheitrum C, Lee I-O, Maack C, Rucker-Martin C, Donzeau-Gouge P, Verde I, Llach A, Hove-Madsen L, Conti M, Vandecasteele G, Fischmeister R (2012) Cyclic adenosine monophosphate phosphodiesterase type 4 protects against atrial arrhythmias. J Am Coll Cardiol 59(24):2182–2190. doi: 10.1016/j.jacc.2012.01.060 CrossRefPubMedGoogle Scholar
  157. Mongillo M, Tocchetti CG, Terrin A, Lissandron V, Cheung Y-F, Dostmann WR, Pozzan T, Kass DA, Paolocci N, Houslay MD (2006) Compartmentalized phosphodiesterase-2 activity blunts β-adrenergic cardiac inotropy via an NO/cGMP-dependent pathway. Circ Res 98(2):226–234Google Scholar
  158. Movsesian MA, Smith CJ, Krall J, Bristow MR, Manganiello VC (1991) Sarcoplasmic reticulum-associated cyclic adenosine 5'-monophosphate phosphodiesterase activity in normal and failing human hearts. J Clin Invest 88(1):15–19. doi: 10.1172/jci115272 CrossRefPubMedPubMedCentralGoogle Scholar
  159. Mubagwa K, Shirayama T, Moreau M, Pappano A (1993) Effects of PDE inhibitors and carbachol on the L-type Ca current in Guinea pig ventricular myocytes. Am J Phys Heart Circ Phys 265(4):H1353–H1363Google Scholar
  160. Mudd JO, Kass DA (2008) Tackling heart failure in the twenty-first century. Nature 451(7181):919–928PubMedGoogle Scholar
  161. Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, Aubin CS, Webster L, Rebeyka IM, Ross DB (2007) Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation 116(3):238–248PubMedGoogle Scholar
  162. Nattel S, Maguy A, Le Bouter S, Yeh Y-H (2007) Arrhythmogenic Ion-Channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev 87(2):425–456. doi: 10.1152/physrev.00014.2006 CrossRefGoogle Scholar
  163. Negroni JA, Morotti S, Lascano EC, Gomes AV, Grandi E, Puglisi JL, Bers DM (2015) β-adrenergic effects on cardiac myofilaments and contraction in an integrated rabbit ventricular myocyte model. J Mol Cell Cardiol 81:162–175PubMedPubMedCentralGoogle Scholar
  164. Neumann J, Scholz H, Döring V, Schmitz W, Meyerinck L, Kalmár P (1988) INCREASE IN MYOCARDIAL G< sub> i−PROTEINS IN HEART FAILURE. Lancet 332(8617):936–937Google Scholar
  165. Nikolaev VO, Bünemann M, Schmitteckert E, Lohse MJ, Engelhardt S (2006) Cyclic AMP imaging in adult cardiac myocytes reveals far-reaching β1-adrenergic but locally confined β2-adrenergic receptor–mediated signaling. Circ Res 99(10):1084–1091. doi: 10.1161/01.RES.0000250046.69918.d5 CrossRefGoogle Scholar
  166. Nikolaev VO, Gambaryan S, Engelhardt S, Walter U, Lohse MJ (2005) Real-time monitoring of the PDE2 activity of live cells: HORMONE-STIMULATED cAMP HYDROLYSIS IS FASTER THAN HORMONE-STIMULATED cAMP SYNTHESIS. J Biol Chem 280(3):1716–1719. doi: 10.1074/jbc.C400505200 CrossRefPubMedGoogle Scholar
  167. Nikolaev VO, Moshkov A, Lyon AR, Miragoli M, Novak P, Paur H, Lohse MJ, Korchev YE, Harding SE, Gorelik J (2010) β2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science 327(5973):1653–1657Google Scholar
  168. Nishikimi T, Maeda N, Matsuoka H (2006) The role of natriuretic peptides in cardioprotection. Cardiovasc Res 69(2):318–328. doi: 10.1016/j.cardiores.2005.10.001 CrossRefPubMedGoogle Scholar
  169. (2014. Web. 1 Apr 2016.) Nobel Media AB.
  170. Noble D, Rudy Y (2001) Models of cardiac ventricular action potentials: iterative interaction between experiment and simulation. Philos Trans Royal Soc London A Mathematical Phys Eng Sci 359(1783):1127–1142. doi: 10.1098/rsta.2001.0820 CrossRefGoogle Scholar
  171. Oliveira RF, Terrin A, Di Benedetto G, Cannon RC, Koh W, Kim M, Zaccolo M, Blackwell KT (2010) The role of type 4 phosphodiesterases in generating microdomains of cAMP: large scale stochastic simulations. PLoS One 5(7):e11725PubMedPubMedCentralGoogle Scholar
  172. Omori K, Kotera J (2007) Overview of PDEs and their regulation. Circ Res 100(3):309–327PubMedGoogle Scholar
  173. Pandit J, Forman MD, Fennell KF, Dillman KS, Menniti FS (2009) Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proc Natl Acad Sci 106(43):18225–18230. doi: 10.1073/pnas.0907635106 CrossRefPubMedGoogle Scholar
  174. Perera RK, Nikolaev VO (2013) Compartmentation of cAMP signalling in cardiomyocytes in health and disease. Acta PhysiologicaGoogle Scholar
  175. Perera RK, Sprenger JU, Steinbrecher JH, Hübscher D, Lehnart SE, Abesser M, Schuh K, El-Armouche A, Nikolaev VO (2015) Microdomain switch of cGMP-regulated phosphodiesterases leads to ANP-induced augmentation of β-adrenoceptor-stimulated contractility in early cardiac hypertrophy. Circ Res 116(8):1304–1311. doi: 10.1161/circresaha.116.306082 CrossRefGoogle Scholar
  176. Perry SJ, Baillie GS, Kohout TA, McPhee I, Magiera MM, Ang KL, Miller WE, McLean AJ, Conti M, Houslay MD (2002) Targeting of cyclic AMP degradation to β2-adrenergic receptors by β-arrestins. Science 298(5594):834–836PubMedGoogle Scholar
  177. Philippides A, Husbands P, O'Shea M (2000) Four-dimensional neuronal signaling by nitric oxide: a computational analysis. The. J Neurosci 20(3):1199–1207PubMedPubMedCentralGoogle Scholar
  178. Pierkes M, Gambaryan S, Bokník P, Lohmann SM, Schmitz W, Potthast R, Holtwick R, Kuhn M (2002) Increased effects of C-type natriuretic peptide on cardiac ventricular contractility and relaxation in guanylyl cyclase A-deficient mice. Cardiovasc Res 53(4):852–861PubMedGoogle Scholar
  179. Piggott LA, Hassell KA, Berkova Z, Morris AP, Silberbach M, Rich TC (2006) Natriuretic peptides and nitric oxide stimulate cGMP synthesis in different cellular compartments. J Gen Physiol 128(1):3–14. doi: 10.1085/jgp.200509403 CrossRefPubMedPubMedCentralGoogle Scholar
  180. Pokreisz P, Vandenwijngaert S, Bito V, Van den Bergh A, Lenaerts I, Busch C, Marsboom G, Gheysens O, Vermeersch P, Biesmans L (2009) Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice. Circulation 119(3):408–416PubMedPubMedCentralGoogle Scholar
  181. Prigent A, Fougier S, Nemoz G, Anker G, Pacheco H, Lugnier C, Lebec A, Stoclet J (1988) Comparison of cyclic nucleotide phosphodiesterase isoforms from rat heart and bovine aorta: separation and inhibition by selective reference phosphodiesterase inhibitors. Biochem Pharmacol 37(19):3671–3681PubMedGoogle Scholar
  182. Rahnama'i MS, Ückert S, Hohnen R, van Koeveringe GA (2013) The role of phosphodiesterases in bladder pathophysiology. Nat Rev Urol 10(7):414–424PubMedGoogle Scholar
  183. Ramamurthi A, Lewis RS (1997) Measurement and modeling of nitric oxide release rates for nitric oxide donors. Chem Res Toxicol 10(4):408–413. doi: 10.1021/tx960183w CrossRefPubMedGoogle Scholar
  184. Reiken S, Gaburjakova M, Guatimosim S, Gomez AM, D'Armiento J, Burkhoff D, Wang J, Vassort G, Lederer WJ, Marks AR (2003) Protein kinase a phosphorylation of the cardiac calcium Release Channel (ryanodine receptor) in normal and failing hearts: ROLE OF PHOSPHATASES AND RESPONSE TO ISOPROTERENOL. J Biol Chem 278(1):444–453. doi: 10.1074/jbc.M207028200 CrossRefPubMedGoogle Scholar
  185. Rich TC, Webb KJ, Leavesley SJ (2014) Can we decipher the information content contained within cyclic nucleotide signals? J Gen Physiol 143(1):17–27. doi: 10.1085/jgp.201311095 CrossRefPubMedPubMedCentralGoogle Scholar
  186. Richard HC (2001) Computational models of normal and abnormal action potential propagation in cardiac tissue: linking experimental and clinical cardiology. Physiol Meas 22(3):R15Google Scholar
  187. Riegger G, Elsner D, Kromer E, Daffner C, Forssmann WG, Muders F, Pascher E, Kochsiek K (1988) Atrial natriuretic peptide in congestive heart failure in the dog: plasma levels, cyclic guanosine monophosphate, ultrastructure of atrial myoendocrine cells, and hemodynamic, hormonal, and renal effects. Circulation 77(2):398–406PubMedGoogle Scholar
  188. Roberts BN, Yang P-C, Behrens SB, Moreno JD, Clancy CE (2012) Computational approaches to understand cardiac electrophysiology and arrhythmias. Am J Physiol Heart Circ Physiol 303(7):H766–H783. doi: 10.1152/ajpheart.01081.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  189. Rochais F, Abi-Gerges A, Horner K, Lefebvre F, Cooper DM, Conti M, Fischmeister R, Vandecasteele G (2006) A specific pattern of phosphodiesterases controls the cAMP signals generated by different Gs-coupled receptors in adult rat ventricular myocytes. Circ Res 98(8):1081–1088PubMedPubMedCentralGoogle Scholar
  190. Rochais F, Vandecasteele G, Lefebvre F, Lugnier C, Lum H, Mazet J-L, Cooper DMF, Fischmeister R (2004) Negative feedback exerted by cAMP-dependent protein kinase and cAMP phosphodiesterase on Subsarcolemmal cAMP signals in intact cardiac myocytes: AN IN VIVO STUDY USING ADENOVIRUS-MEDIATED EXPRESSION OF CNG CHANNELS. J Biol Chem 279(50):52095–52105. doi: 10.1074/jbc.M405697200 CrossRefPubMedGoogle Scholar
  191. Roy B, Garthwaite J (2006) Nitric oxide activation of guanylyl cyclase in cells revisited. Proc Natl Acad Sci 103(32):12185–12190PubMedGoogle Scholar
  192. Roy B, Halvey EJ, Garthwaite J (2008) An enzyme-linked receptor mechanism for nitric oxide-activated guanylyl cyclase. J Biol Chem 283(27):18841–18851PubMedGoogle Scholar
  193. Russell TR, Terasaki WL, Appleman MM (1973) Separate phosphodiesterases for the hydrolysis of cyclic adenosine 3',5'-monophosphate and cyclic guanosine 3',5'-monophosphate in rat liver. J Biol Chem 248(4):1334–1340PubMedGoogle Scholar
  194. Ryall KA, Holland DO, Delaney KA, Kraeutler MJ, Parker AJ, Saucerman JJ (2012) Network reconstruction and systems analysis of cardiac myocyte hypertrophy signaling. J Biol Chem 287(50):42259–42268. doi: 10.1074/jbc.M112.382937 CrossRefPubMedPubMedCentralGoogle Scholar
  195. Rybalkin SD, Rybalkina IG, Feil R, Hofmann F, Beavo JA (2002) Regulation of cGMP-specific phosphodiesterase (PDE5) phosphorylation in smooth muscle cells. J Biol Chem 277(5):3310–3317PubMedGoogle Scholar
  196. Rybin VO, Xu X, Lisanti MP, Steinberg SF (2000) Differential targeting of β-adrenergic receptor subtypes and adenylyl cyclase to cardiomyocyte caveolae a mechanism to functionally regulate the cAMP signaling pathway. J Biol Chem 275(52):41447–41457PubMedGoogle Scholar
  197. Sato N, Asai K, Okumura S, Takagi G, Shannon RP, Fujita-Yamaguchi Y, Ishikawa Y, Vatner SF, Vatner DE (1999) Mechanisms of desensitization to a PDE inhibitor (milrinone) in conscious dogs with heart failure. Am J Physiol Heart Circ Physiol 276(5):H1699–H1705Google Scholar
  198. Saucerman JJ, Brunton LL, Michailova AP, McCulloch AD (2003) Modeling β-adrenergic control of cardiac myocyte contractility in Silico. J Biol Chem 278(48):47997–48003. doi: 10.1074/jbc.M308362200 CrossRefPubMedGoogle Scholar
  199. Saucerman JJ, Greenwald EC, Polanowska-Grabowska R (2014) Mechanisms of cyclic AMP compartmentation revealed by computational models. J Gen Physiol 143(1):39–48. doi: 10.1085/jgp.201311044 CrossRefPubMedPubMedCentralGoogle Scholar
  200. Saucerman JJ, Healy SN, Belik ME, Puglisi JL, McCulloch AD (2004) Proarrhythmic consequences of a KCNQ1 AKAP-binding domain mutation: computational models of whole cells and heterogeneous tissue. Circ Res 95(12):1216–1224. doi: 10.1161/01.RES.0000150055.06226.4e CrossRefGoogle Scholar
  201. Saucerman JJ, McCulloch AD (2004) Mechanistic systems models of cell signaling networks: a case study of myocyte adrenergic regulation. Prog Biophys Mol Biol 85(2):261–278PubMedGoogle Scholar
  202. Saucerman JJ, McCulloch AD (2006) Cardiac β-adrenergic signaling. Ann N Y Acad Sci 1080(1):348–361. doi: 10.1196/annals.1380.026 CrossRefPubMedGoogle Scholar
  203. Schmidt K, Desch W, Klatt P, Kukovetz WR, Mayer B (1997) Release of nitric oxide from donors with known half-life: a mathematical model for calculating nitric oxide concentrations in aerobic solutions. Naunyn Schmiedeberg's Arch Pharmacol 355(4):457–462. doi: 10.1007/pl00004969 CrossRefGoogle Scholar
  204. Schröder F, Handrock R, Beuckelmann DJ, Hirt S, Hullin R, Priebe L, Schwinger RHG, Weil J, Herzig S (1998) Increased availability and open probability of single L-type calcium channels from failing compared with nonfailing human ventricle. Circulation 98(10):969–976. doi: 10.1161/01.cir.98.10.969 CrossRefPubMedGoogle Scholar
  205. Schröder F, Klein G, Fiedler B, Bastein M, Schnasse N, Hillmer A, Ames S, Gambaryan S, Drexler H, Walter U (2003) Single L-type Ca2+ channel regulation by cGMP-dependent protein kinase type I in adult cardiomyocytes from PKG I transgenic mice. Cardiovasc Res 60(2):268–277PubMedGoogle Scholar
  206. Senzaki H, Smith CJ, Juang GJ, Isoda T, Mayer SP, Ohler A, Paolocci N, Tomaselli GF, Hare JM, Kass DA (2001) Cardiac phosphodiesterase 5 (cGMP-specific) modulates β-adrenergic signaling in vivo and is down-regulated in heart failure. FASEB J 15(10):1718–1726. doi: 10.1096/fj.00-0538com CrossRefGoogle Scholar
  207. Sette C, Conti M (1996) Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP-dependent protein kinase INVOLVEMENT OF SERINE 54 IN THE ENZYME ACTIVATION. J Biol Chem 271(28):16526–16534PubMedGoogle Scholar
  208. Shah AM, Spurgeon HA, Sollott SJ, Talo A, Lakatta EG (1994) 8-bromo-cGMP reduces the myofilament response to Ca2+ in intact cardiac myocytes. Circ Res 74(5):970–978PubMedGoogle Scholar
  209. Shaw RM, Colecraft HM (2013) L-type calcium channel targeting and local signalling in cardiac myocytes. Cardiovasc Res 98(2):177–186. doi: 10.1093/cvr/cvt021 CrossRefPubMedPubMedCentralGoogle Scholar
  210. Shirayama T, Pappano AJ (1996) Biphasic effects of intrapipette cyclic guanosine monophosphate on L-type calcium current and contraction of Guinea pig ventricular myocytes. J Pharmacol Exp Ther 279(3):1274–1281PubMedGoogle Scholar
  211. Simmons MA, Hartzell HC (1988) Role of phosphodiesterase in regulation of calcium current in isolated cardiac myocytes. Mol Pharmacol 33(6):664–671PubMedGoogle Scholar
  212. Smith CJ, He J, Ricketts SG, Ding J-Z, Moggio RA, Hintze TH (1998) Downregulation of right ventricular phosphodiesterase PDE-3A mRNA and protein before the development of canine heart failure. Cell Biochem Biophys 29(1):67–88. doi: 10.1007/bf02737829 CrossRefPubMedGoogle Scholar
  213. Smith NP, Crampin EJ, Niederer SA, Bassingthwaighte JB, Beard DA (2007) Computational biology of cardiac myocytes: proposed standards for the physiome. J Exp Biol 210(9):1576–1583. doi: 10.1242/jeb.000133 CrossRefPubMedPubMedCentralGoogle Scholar
  214. Soderling SH, Bayuga SJ, Beavo JA (1998) Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. J Biol Chem 273(25):15553–15558PubMedGoogle Scholar
  215. Solaro RJ, Kobayashi T (2011) Protein phosphorylation and signal transduction in cardiac thin filaments. J Biol Chem 286(12):9935–9940. doi: 10.1074/jbc.R110.197731 CrossRefPubMedPubMedCentralGoogle Scholar
  216. Soltis AR, Saucerman JJ (2010) Synergy between CaMKII substrates and β-adrenergic signaling in regulation of cardiac myocyte Ca 2+ handling. Biophys J 99(7):2038–2047PubMedPubMedCentralGoogle Scholar
  217. Song L-S, Wang S-Q, Xiao R-P, Spurgeon H, Lakatta EG, Cheng H (2001) β-adrenergic stimulation synchronizes intracellular Ca2+ release during excitation-contraction coupling in cardiac myocytes. Circ Res 88(8):794–801. doi: 10.1161/hh0801.090461 CrossRefPubMedGoogle Scholar
  218. Sprenger JU, Nikolaev VO (2013) Biophysical techniques for detection of cAMP and cGMP in living cells. Int J Mol Sci 14(4):8025–8046. doi: 10.3390/ijms14048025 CrossRefPubMedPubMedCentralGoogle Scholar
  219. Stangherlin A, Gesellchen F, Zoccarato A, Terrin A, Fields LA, Berrera M, Surdo NC, Craig MA, Smith G, Hamilton G (2011) cGMP signals modulate cAMP levels in a compartment-specific manner to regulate catecholamine-dependent signaling in cardiac MyocytesNovelty and significance. Circ Res 108(8):929–939PubMedPubMedCentralGoogle Scholar
  220. Stangherlin A, Zaccolo M (2012) cGMP-cAMP interplay in cardiac myocytes: a local affair with far-reaching consequences for heart function. Biochem Soc Trans 40(1):11–14. doi: 10.1042/BST20110655 CrossRefGoogle Scholar
  221. Sumii K, Sperelakis N (1995) cGMP-dependent protein kinase regulation of the L-type Ca2+ current in rat ventricular myocytes. Circ Res 77(4):803–812. doi: 10.1161/01.res.77.4.803 CrossRefPubMedGoogle Scholar
  222. Takimoto E (2012) Cyclic GMP-dependent signaling in cardiac myocytes. Circ J 76(8):1819–1825PubMedGoogle Scholar
  223. Takimoto E, Belardi D, Tocchetti CG, Vahebi S, Cormaci G, Ketner EA, Moens AL, Champion HC, Kass DA (2007) Compartmentalization of cardiac β-adrenergic inotropy modulation by phosphodiesterase type 5. Circulation 115(16):2159–2167Google Scholar
  224. Takimoto E, Champion HC, Belardi D, Moslehi J, Mongillo M, Mergia E, Montrose DC, Isoda T, Aufiero K, Zaccolo M, Dostmann WR, Smith CJ, Kass DA (2005a) cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism. Circ Res 96(1):100–109. doi: 10.1161/01.res.0000152262.22968.72 CrossRefPubMedGoogle Scholar
  225. Takimoto E, Champion HC, Li M, Ren S, Rodriguez ER, Tavazzi B, Lazzarino G, Paolocci N, Gabrielson KL, Wang Y (2005b) Oxidant stress from nitric oxide synthase–3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load. J Clin Invest 115(5):1221–1231PubMedPubMedCentralGoogle Scholar
  226. Tamargo J, Caballero R, Gómez R, Delpón E (2010) Cardiac electrophysiological effects of nitric oxide. Cardiovasc Res 87(4):593–600. doi: 10.1093/cvr/cvq214 CrossRefPubMedGoogle Scholar
  227. Terrenoire C, Clancy CE, Cormier JW, Sampson KJ, Kass RS (2005) Autonomic control of cardiac action potentials role of Potassium Channel kinetics in response to sympathetic stimulation. Circ Res 96(5):e25–e34Google Scholar
  228. Terrenoire C, Houslay MD, Baillie GS, Kass RS (2009) The cardiac IKs Potassium Channel macromolecular complex includes the phosphodiesterase PDE4D3. J Biol Chem 284(14):9140–9146. doi: 10.1074/jbc.M805366200 CrossRefPubMedPubMedCentralGoogle Scholar
  229. Tohse N, Nakaya H, Kanno YT (1995) Cyclic GMP-mediated inhibition of L-type Ca2+ channel activity by human natriuretic peptide in rabbit heart cells. Br J Pharmacol 114(5):1076–1082PubMedPubMedCentralGoogle Scholar
  230. Tohse N, Sperelakis N (1991) cGMP inhibits the activity of single calcium channels in embryonic chick heart cells. Circ Res 69(2):325–331. doi: 10.1161/01.res.69.2.325 CrossRefPubMedGoogle Scholar
  231. Tomaselli GF, Marbán E (1999) Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc Res 42(2):270–283. doi: 10.1016/s0008-6363(99)00017-6 CrossRefPubMedGoogle Scholar
  232. Trayanova NA, Rice JJ (2011) Cardiac electromechanical models: from cell to organ. Front Physiol 2. doi: 10.3389/fphys.2011.00043
  233. Tsai EJ, Kass DA (2009) Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics. Pharmacol Ther 122(3):216–238. doi: 10.1016/j.pharmthera.2009.02.009 CrossRefPubMedPubMedCentralGoogle Scholar
  234. Tsai EJ, Liu Y, Koitabashi N, Bedja D, Danner T, Jasmin J-F, Lisanti MP, Friebe A, Takimoto E, Kass DA (2012) Pressure-overload–induced subcellular Relocalization/oxidation of soluble guanylyl cyclase in the heart modulates enzyme stimulation. Circ Res 110(2):295–303Google Scholar
  235. Tsoukias NM (2008) Nitric oxide bioavailability in the microcirculation: insights from mathematical models. Microcirculation 15(8):813–834PubMedGoogle Scholar
  236. Tsoukias NM, Kavdia M, Popel AS (2004) A theoretical model of nitric oxide transport in arterioles: frequency- vs. amplitude-dependent control of cGMP formation. Am J Physiol Heart Circ Physiol 286(3):H1043–H1056. doi: 10.1152/ajpheart.00525.2003 CrossRefPubMedGoogle Scholar
  237. Tsutamoto T, Kanamori T, Wada A, Kinoshita M (1992) Uncoupling of atrial natriuretic peptide extraction and cyclic guanosine monophosphate production in the pulmonary circulation in patients with severe heart failure. J Am Coll Cardiol 20(3):541–546PubMedGoogle Scholar
  238. Ungerer M, Böhm M, Elce J, Erdmann E, Lohse M (1993) Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. Circulation 87(2):454–463PubMedGoogle Scholar
  239. van Heerebeek L, Hamdani N, Falcão-Pires I, Leite-Moreira AF, Begieneman MP, Bronzwaer JG, van der Velden J, Stienen GJ, Laarman GJ, Somsen A (2012) Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 126(7):830–839PubMedGoogle Scholar
  240. Vandecasteele G, Rochais F, Abi-Gerges A, Fischmeister R (2006) Functional localization of cAMP signalling in cardiac myocytes. Biochem Soc Trans 34(4):484–488PubMedGoogle Scholar
  241. Verde I, Pahlke G, Salanova M, Zhang G, Wang S, Coletti D, Onuffer J, Jin S-LC, Conti M (2001) Myomegalin is a novel protein of the Golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase. J Biol Chem 276(14):11189–11198. doi: 10.1074/jbc.M006546200 CrossRefPubMedGoogle Scholar
  242. Verde I, Vandecasteele G, Lezoualc'h F, Fischmeister R (1999) Characterization of the cyclic nucleotide phosphodiesterase subtypes involved in the regulation of the L-type Ca2+ current in rat ventricular myocytes. Br J Pharmacol 127(1):65–74PubMedPubMedCentralGoogle Scholar
  243. Vila-Petroff MG, Younes A, Egan J, Lakatta EG, Sollott SJ (1999) Activation of distinct cAMP-dependent and cGMP-dependent pathways by nitric oxide in cardiac myocytes. Circ Res 84(9):1020–1031Google Scholar
  244. Wahler GM, Dollinger SJ (1995) Nitric oxide donor SIN-1 inhibits mammalian cardiac calcium current through cGMP-dependent protein kinase. Am J Phys Cell Phys 268(1):C45–C54Google Scholar
  245. Wang H, Kohr MJ, Traynham CJ, Ziolo MT (2009) Phosphodiesterase 5 restricts NOS3/soluble guanylate cyclase signaling to L-type Ca2+ current in cardiac myocytes. J Mol Cell Cardiol 47(2):304–314. doi: 10.1016/j.yjmcc.2009.03.021 CrossRefPubMedPubMedCentralGoogle Scholar
  246. Warrier S, Ramamurthy G, Eckert RL, Nikolaev VO, Lohse MJ, Harvey RD (2007) cAMP microdomains and L-type Ca2+ channel regulation in Guinea-pig ventricular myocytes. J Physiol 580(3):765–776PubMedPubMedCentralGoogle Scholar
  247. Wegener A, Simmerman H, Lindemann J, Jones LR (1989) Phospholamban phosphorylation in intact ventricles. Phosphorylation of serine 16 and threonine 17 in response to beta-adrenergic stimulation. J Biol Chem 264(19):11468–11474PubMedGoogle Scholar
  248. Weishaar RE, Kobylarz-Singer DC, Steffen RP, Kaplan HR (1987) Subclasses of cyclic AMP-specific phosphodiesterase in left ventricular muscle and their involvement in regulating myocardial contractility. Circ Res 61(4):539–547PubMedGoogle Scholar
  249. Weiss HR, Gong GX, Straznicka M, Yan L, Tse J, Scholz PM (1999) Cyclic GMP and cyclic AMP induced changes in control and hypertrophic cardiac myocyte function interact through cyclic GMP affected cyclic-AMP phosphodiesterases. Can J Physiol Pharmacol 77(6):422–431PubMedGoogle Scholar
  250. Williams GSB, Smith GD, Sobie EA, Jafri MS (2010) Models of cardiac excitation–contraction coupling in ventricular myocytes. Math Biosci 226(1):1–15. doi: 10.1016/j.mbs.2010.03.005 CrossRefPubMedPubMedCentralGoogle Scholar
  251. Winslow RL, Cortassa S, O'Rourke B, Hashambhoy YL, Rice JJ, Greenstein JL (2011) Integrative modeling of the cardiac ventricular myocyte. Wiley Interdiscip Rev Syst Biol Med 3(4):392–413PubMedGoogle Scholar
  252. Winslow RL, Greenstein JL, Tomaselli GF, O’Rourke B (2001) Computational models of the failing myocyte: relating altered gene expression to cellular function. Philos Trans R Soc London, Ser A 359(1783):1187–1200. doi: 10.1098/rsta.2001.0825 CrossRefGoogle Scholar
  253. Winslow RL, Rice J, Jafri S (1998) Modeling the cellular basis of altered excitation–contraction coupling in heart failure. Prog Biophys Mol Biol 69(2–3):497–514. doi: 10.1016/S0079-6107(98)00022-4 CrossRefPubMedGoogle Scholar
  254. Winslow RL, Trayanova N, Geman D, Miller MI (2012) Computational medicine: translating models to clinical care. Science Translational Medicine 4 (158):158rv111-158rv111PubMedPubMedCentralGoogle Scholar
  255. Winslow RL, Walker MA, Greenstein JL (2016) Modeling calcium regulation of contraction, energetics, signaling, and transcription in the cardiac myocyte. Wiley Interdiscip Rev Syst Biol Med 8(1):37–67PubMedGoogle Scholar
  256. Wollert KC, Drexler H (2002) Regulation of cardiac remodeling by nitric oxide: focus on cardiac myocyte hypertrophy and apoptosis. Heart Fail Rev 7(4):317–325PubMedGoogle Scholar
  257. Wu AY, Tang X-B, Martinez SE, Ikeda K, Beavo JA (2004) Molecular determinants for cyclic nucleotide binding to the regulatory domains of phosphodiesterase 2A. J Biol Chem 279(36):37928–37938. doi: 10.1074/jbc.M404287200 CrossRefPubMedGoogle Scholar
  258. Xie Y, Grandi E, Puglisi JL, Sato D, Bers DM (2013) β-adrenergic stimulation activates early afterdepolarizations transiently via kinetic mismatch of PKA targets. J Mol Cell Cardiol 58:153–161PubMedPubMedCentralGoogle Scholar
  259. Xin W, Tran TM, Richter W, Clark RB, Rich TC (2008) Roles of GRK and PDE4 activities in the regulation of β2 adrenergic signaling. J Gen Physiol 131(4):349–364. doi: 10.1085/jgp.200709881 CrossRefPubMedPubMedCentralGoogle Scholar
  260. Xu H, Ginsburg KS, Hall DD, Zimmermann M, Stein IS, Zhang M, Tandan S, Hill JA, Horne MC, Bers D (2010) Targeting of protein phosphatases PP2A and PP2B to the C-terminus of the L-type calcium channel Cav1. 2. Biochemistry 49(48):10298–10307PubMedPubMedCentralGoogle Scholar
  261. Yan C, Ding B, Shishido T, Woo C-H, Itoh S, Jeon K-I, Liu W, Xu H, McClain C, Molina CA (2007a) Activation of extracellular signal-regulated kinase 5 reduces cardiac apoptosis and dysfunction via inhibition of a phosphodiesterase 3A/inducible cAMP early repressor feedback loop. Circ Res 100(4):510–519PubMedPubMedCentralGoogle Scholar
  262. Yan C, Miller CL, J-i A (2007b) Regulation of phosphodiesterase 3 and inducible cAMP early repressor in the heart. Circ Res 100(4):489–501PubMedPubMedCentralGoogle Scholar
  263. Yan C, Zhao AZ, Bentley JK, Beavo JA (1996) The calmodulin-dependent phosphodiesterase Gene PDE1C encodes several functionally different splice variants in a tissue-specific manner. J Biol Chem 271(41):25699–25706PubMedGoogle Scholar
  264. Yang J, Clark JW, Bryan RM, Robertson CS (2005) Mathematical modeling of the nitric oxide/cGMP pathway in the vascular smooth muscle cell. Am J Phys Heart Circ Phys 289(2):H886–H897Google Scholar
  265. Yang JH, Polanowska-Grabowska RK, Smith JS, Shields Iv CW, Saucerman JJ (2014) PKA catalytic subunit compartmentation regulates contractile and hypertrophic responses to β-adrenergic signaling. J Mol Cell Cardiol 66:83–93. doi: 10.1016/j.yjmcc.2013.11.001 CrossRefPubMedGoogle Scholar
  266. Yang JH, Saucerman JJ (2012) Phospholemman is a negative feed-forward regulator of Ca2+ in β-adrenergic signaling, accelerating β-adrenergic inotropy. J Mol Cell Cardiol 52(5):1048–1055PubMedPubMedCentralGoogle Scholar
  267. Yang L, Liu G, Zakharov SI, Bellinger AM, Mongillo M, Marx SO (2007) Protein kinase G phosphorylates Cav1. 2 α1c and β2 subunits. Circ Res 101(5):465–474PubMedGoogle Scholar
  268. Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougasaki M, Ogawa H, Okumura K, Mukoyama M, Nakao K (1994) Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 90(1):195–203. doi: 10.1161/01.cir.90.1.195 CrossRefPubMedGoogle Scholar
  269. Yue DT, Herzig S, Marban E (1990) Beta-adrenergic stimulation of calcium channels occurs by potentiation of high-activity gating modes. Proc Natl Acad Sci 87(2):753–757PubMedGoogle Scholar
  270. Zaccolo M, Movsesian MA (2007) cAMP and cGMP signaling cross-talk role of phosphodiesterases and implications for cardiac pathophysiology. Circ Res 100(11):1569–1578Google Scholar
  271. Zakhary DR, Moravec CS, Stewart RW, Bond M (1999) Protein kinase a (PKA)-dependent troponin-I phosphorylation and PKA regulatory subunits are decreased in human dilated cardiomyopathy. Circulation 99(4):505–510PubMedGoogle Scholar
  272. Zhang M, Koitabashi N, Nagayama T, Rambaran R, Feng N, Takimoto E, Koenke T, O'Rourke B, Champion HC, Crow MT, Kass DA (2008) Expression, activity, and pro-hypertrophic effects of PDE5A in cardiac myocytes. Cell Signal 20(12):2231–2236. doi: 10.1016/j.cellsig.2008.08.012 CrossRefPubMedPubMedCentralGoogle Scholar
  273. Zhang M, Takimoto E, Lee D-i, Santos CX, Nakamura T, Hsu S, Jiang A, Nagayama T, Bedja D, Yuan Y (2012) Pathological cardiac hypertrophy alters intracellular targeting of phosphodiesterase type 5 from nitric oxide synthase-3 to natriuretic peptide signaling. Circulation 126(8):942–951PubMedPubMedCentralGoogle Scholar
  274. Zhao CY, Greenstein JL, Winslow RL (2015) Interaction between phosphodiesterases in the regulation of the cardiac β-adrenergic pathway. J Mol Cell Cardiol 88:29–38. doi: 10.1016/j.yjmcc.2015.09.011 CrossRefPubMedPubMedCentralGoogle Scholar
  275. Zhao CY, Greenstein JL, Winslow RL (2016a) Regulation of the Cardiac L-Type Calcium Channel by the Cyclic Nucleotide Cross-Talk Signaling Network. Biophysical Journal 110 (3):359a. doi: 10.1016/j.bpj.2015.11.1937 Google Scholar
  276. Zhao CY, Greenstein JL, Winslow RL (2016b) Roles of phosphodiesterases in the regulation of the cardiac cyclic nucleotide cross-talk signaling network. J Mol Cell Cardiol 91:215–227. doi: 10.1016/j.yjmcc.2016.01.004 CrossRefPubMedPubMedCentralGoogle Scholar
  277. Ziolo MT, Harshbarger CH, Roycroft KE, Smith JM, Romano FD, Sondgeroth KL, Wahler GM (2001) Myocytes isolated from rejecting transplanted rat hearts exhibit a nitric oxide-mediated reduction in the calcium current. J Mol Cell Cardiol 33(9):1691–1699PubMedGoogle Scholar
  278. Ziolo MT, Kohr MJ, Wang H (2008) Nitric oxide signaling and the regulation of myocardial function. J Mol Cell Cardiol 45(5):625–632PubMedPubMedCentralGoogle Scholar
  279. Ziolo MT, Lewandowski SJ, Smith JM, Romano FD, Wahler GM (2003) Inhibition of cyclic GMP hydrolysis with zaprinast reduces basal and cyclic AMP-elevated L-type calcium current in Guinea-pig ventricular myocytes. Br J Pharmacol 138(5):986–994PubMedPubMedCentralGoogle Scholar
  280. Zoraghi R, Corbin JD, Francis SH (2004) Properties and functions of GAF domains in cyclic nucleotide phosphodiesterases and other proteins. Mol Pharmacol 65(2):267–278PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Department of Biomedical EngineeringInstitute for Computational Medicine, The Johns Hopkins University School of Medicine and Whiting School of EngineeringBaltimoreUSA
  2. 2.Acute Care Solutions, Philips Research North AmericaCambridgeUSA

Personalised recommendations