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Compartmentalized cAMP/PKA signalling regulates cardiac excitation–contraction coupling

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Abstract

The sympathetic control over excitation–contraction coupling (ECC) is mediated by the cAMP/PKA signalling pathway. However, in the myocyte, the same signalling pathway is responsible for triggering a plethora of diverse intracellular functions the control of which must be independent of the regulation of ECC. Here we discuss what are the molecular mechanisms leading to selective modulation of ECC in cardiac myocytes with a particular focus on the role of spatial confinement of PKA subsets and the compartmentalization of cAMP.

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References

  • Bacskai BJ, Hochner B, Mahaut-Smith M, Adams SR, Kaang BK, Kandel ER, Tsien RY (1993) Spatially resolved dynamics of cAMP and protein kinase A subunits in Aplysia sensory neurons. Science 260:222–226

    PubMed  CAS  ADS  Google Scholar 

  • Baillie GS, Scott JD, Houslay MD (2005) Compartmentalisation of phosphodiesterases and protein kinase A: opposites attract. FEBS Lett 579:3264–3270

    Article  PubMed  CAS  Google Scholar 

  • Bers DM, Perez-Reyes E. (1999) Ca channels in cardiac myocytes: structure and function in Ca influx and intracellular Ca release. Cardiovasc Res 42:339–360

    Article  PubMed  CAS  Google Scholar 

  • Carr DW, Stofko-Hahn RE, Fraser ID, Bishop SM, Acott TS, Brennan RG, Scott JD (1991) Interaction of the regulatory subunit (RII) of cAMP-dependent protein kinase with RII-anchoring proteins occurs through an amphipathic helix binding motif. J Biol Chem 266:14188–14192

    PubMed  CAS  Google Scholar 

  • Chen L, Kurokawa J, Kass RS (2005) Phosphorylation of the A-kinase-anchoring protein Yotiao contributes to protein kinase A regulation of a heart potassium channel. J Biol Chem 280:31347–31352

    Article  PubMed  CAS  Google Scholar 

  • Diviani D, Soderling J, Scott JD (2001) AKAP-Lbc anchors protein kinase A and nucleates Galpha 12-selective Rho-mediated stress fiber formation. J Biol Chem 276:44247–44257

    Article  PubMed  CAS  Google Scholar 

  • Dodge-Kafka KL, Langeberg L, Scott JD (2006) Compartmentation of cyclic nucleotide signaling in the heart: the role of A-kinase anchoring proteins. Circ Res 98:993–1001

    Article  PubMed  CAS  Google Scholar 

  • 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 20:1921–1930

    Article  PubMed  CAS  Google Scholar 

  • Dransfield DT, Bradford AJ, Smith J, Martin M, Roy C, Mangeat PH, Goldenring JR (1997) Ezrin is a cyclic AMP-dependent protein kinase anchoring protein. Embo J 16:35–43

    Article  PubMed  CAS  Google Scholar 

  • Garvey JL, Kranias EG, Solaro RJ (1988) Phosphorylation of C-protein, troponin I and phospholamban in isolated rabbit hearts. Biochem J 249:709–714

    PubMed  CAS  Google Scholar 

  • Gautel M, Zuffardi O, Freiburg A, Labeit S. (1995) Phosphorylation switches specific for the cardiac isoform of myosin binding protein-C: a modulator of cardiac contraction?. Embo J 14:1952–1960

    PubMed  CAS  Google Scholar 

  • Gray PC, Johnson BD, Westenbroek RE, Hays LG, Yates JR III, Scheuer T, Catterall WA, Murphy BJ (1998) Primary structure and function of an A kinase anchoring protein associated with calcium channels. Neuron 20:1017–1026

    Article  PubMed  CAS  Google Scholar 

  • Hagemann D, Xiao RP (2002) Dual site phospholamban phosphorylation and its physiological relevance in the heart. Trends Cardiovasc Med 12:51–56

    Article  PubMed  CAS  Google Scholar 

  • Hanoune J, Defer N (2001) Regulation and role of adenylyl cyclase isoforms. Annu Rev Pharmacol Toxicol 41:145–174

    Article  PubMed  CAS  Google Scholar 

  • Hayes JS, Brunton LL, Mayer SE (1980) Selective activation of particulate cAMP-dependent protein kinase by isoproterenol and prostaglandin E1. J Biol Chem 255:5113–5119

    PubMed  CAS  Google Scholar 

  • Houslay MD, Adams DR (2003) PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J 370:1–18

    Article  PubMed  CAS  Google Scholar 

  • Huang C, Hepler JR, Chen LT, Gilman AG, Anderson RG, Mumby SM (1997) Organization of G proteins and adenylyl cyclase at the plasma membrane. Mol Biol Cell 8:2365–2378

    PubMed  CAS  Google Scholar 

  • Hulme JT, Lin TW, Westenbroek RE, Scheuer T, Catterall WA (2003) Beta-adrenergic regulation requires direct anchoring of PKA to cardiac CaV1.2 channels via a leucine zipper interaction with A kinase-anchoring protein 15. Proc Natl Acad Sci USA 100:13093–13098

    Article  PubMed  CAS  ADS  Google Scholar 

  • Johnson BD, Scheuer T, Catterall WA (1994) Voltage-dependent potentiation of L-type Ca2+ channels in skeletal muscle cells requires anchored cAMP-dependent protein kinase. Proc Natl Acad Sci USA 91:11492–11496

    Article  PubMed  CAS  ADS  Google Scholar 

  • Jurevicius J, Fischmeister R (1996) cAMP compartmentation is responsible for a local activation of cardiac Ca2+ channels by beta-adrenergic agonists. Proc Natl Acad Sci USA 93:295–299

    Article  PubMed  CAS  ADS  Google Scholar 

  • Kapiloff MS, Jackson N, Airhart N. (2001) mAKAP and the ryanodine receptor are part of a multi-component signaling complex on the cardiomyocyte nuclear envelope. J Cell Sci 114:3167–3176

    PubMed  CAS  Google Scholar 

  • Kapiloff MS (2002) Contributions of protein kinase A anchoring proteins to compartmentation of cAMP signaling in the heart. Mol Pharmacol 62:193–199

    Article  PubMed  CAS  Google Scholar 

  • Karpen JW, Rich TC (2001) The fourth dimension in cellular signaling. Science. 293:2204–2205

    Article  PubMed  CAS  Google Scholar 

  • Kuschel M, Zhou YY, Spurgeon HA, Bartel S, Karczewski P, Zhang SJ, Krause EG, Lakatta EG, Xiao RP (1999) beta2-adrenergic cAMP signaling is uncoupled from phosphorylation of cytoplasmic proteins in canine heart. Circulation 99:2458–2465

    PubMed  CAS  Google Scholar 

  • Lehnart SE, Wehrens XH, Reiken S, Warrier S, Belevych AE, Harvey RD, Richter W, Jin SL, Conti M, Marks AR (2005) Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. Cell 123:25–35

    Article  PubMed  CAS  Google Scholar 

  • Li H, Adamik R, Pacheco-Rodriguez G, Moss J, Vaughan M (2003) Protein kinase A-anchoring (AKAP) domains in brefeldin A-inhibited guanine nucleotide-exchange protein 2 (BIG21). Proc Natl Acad Sci USA 100:1627–1632

    Article  PubMed  CAS  ADS  Google Scholar 

  • MacKenzie SJ, Baillie GS, McPhee I, MacKenzie C, Seamons R, McSorley T, Millen J, Beard MB, van 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 136:421–433

    Article  PubMed  CAS  Google Scholar 

  • Markou T, Hadzopoulou-Cladaras M, Lazou A (2004) Phenylephrine induces activation of CREB in adult rat cardiac myocytes through MSK1 and PKA signaling pathways. J Mol Cell Cardiol 37:1001–1111

    Article  PubMed  CAS  Google Scholar 

  • 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 101:365–376

    Article  PubMed  CAS  Google Scholar 

  • Marx SO, Reiken S, Hisamatsu Y, Gaburjakova M, Gaburjakova J, Yang YM, Rosemblit N, Marks AR (2001) Phosphorylation-dependent regulation of ryanodine receptors: a novel role for leucine/isoleucine zippers. J Cell Biol 153:699–708

    Article  PubMed  CAS  Google Scholar 

  • Marx SO, Kurokawa J, Reiken S, Motoike H, D’Armiento J, Marks AR, Kass RS (2002) Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science 295:496–499

    Article  PubMed  CAS  ADS  Google Scholar 

  • McCartney S, Little BM, Scott JD (1995) Analysis of a novel A-kinase anchoring protein 100:(AKAP 100). Biochem Soc Trans 23:268S

    PubMed  CAS  Google Scholar 

  • Mongillo M, McSorley T, Evellin S, Sood A, Lissandron V, Terrin A, Huston E, Hannawacker A, Lohse MJ, Pozzan T, Houslay MD, Zaccolo M (2004) Fluorescence resonance energy transfer-based analysis of cAMP dynamics in live neonatal rat cardiac myocytes reveals distinct functions of compartmentalized phosphodiesterases. Circ Res 95:67–75

    Article  PubMed  CAS  Google Scholar 

  • Mongillo M, Tocchetti CG, Terrin A, Lissandron V, Cheung YF, Dostmann WR, Pozzan T, Kass DA, Paolocci N, Houslay MD, Zaccolo M (2006) Compartmentalized phosphodiesterase-2 activity blunts beta-adrenergic cardiac inotropy via an NO/cGMP-dependent pathway. Circ Res 98:226–234

    Article  PubMed  CAS  Google Scholar 

  • Nauert JB, Klauck TM, Langeberg LK, Scott JD (1997) Gravin, an autoantigen recognized by serum from myasthenia gravis patients, is a kinase scaffold protein. Curr Biol 7:52–62

    Article  PubMed  CAS  Google Scholar 

  • 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 280:1716–1719

    Article  PubMed  CAS  Google Scholar 

  • Rich TC, Fagan KA, Nakata H, Schaack J, Cooper DM, Karpen JW (2000) Cyclic nucleotide-gated channels colocalize with adenylyl cyclase in regions of restricted cAMP diffusion. J Gen Physiol 116:147–161

    Article  PubMed  CAS  Google Scholar 

  • Rybin VO, Pak E, Alcott S, Steinberg SF (2003) Developmental changes in beta2-adrenergic receptor signaling in ventricular myocytes: the role of Gi proteins and caveolae microdomains. Mol Pharmacol 63:1338–1348

    Article  PubMed  CAS  Google Scholar 

  • Schulze DH, Muqhal M, Lederer WJ, Ruknudin AM (2003) Sodium/calcium exchanger (NCX1) macromolecular complex. J Biol Chem 278:28849–28855

    Article  PubMed  CAS  Google Scholar 

  • 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 271:16526–16534

    Article  PubMed  CAS  Google Scholar 

  • Strang KT, Sweitzer NK, Greaser ML, Moss RL (1994) Beta-adrenergic receptor stimulation increases unloaded shortening velocity of skinned single ventricular myocytes from rats. Circ Res 74:542–549

    PubMed  CAS  Google Scholar 

  • Tasken K, Aandahl EM (2004) Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiol Rev 84:137–167

    Article  PubMed  CAS  Google Scholar 

  • Verboomen H, Wuytack F, De Smedt H, Himpens B, Casteels R (1992) Functional difference between SERCA2a and SERCA2b Ca2+ pumps and their modulation by phospholamban. Biochem J. 286(Pt 2):591–595

    PubMed  CAS  Google Scholar 

  • Vila Petroff MG, Egan JM, Wang X, Sollott SJ (2001) Glucagon-like peptide-1 increases cAMP but fails to augment contraction in adult rat cardiac myocytes. Circ Res 89:445–452

    PubMed  CAS  Google Scholar 

  • Wong W, Scott JD (2004) AKAP signalling complexes: focal points in space and time. Nat Rev Mol Cell Biol 5:959–970

    Article  PubMed  CAS  Google Scholar 

  • Zaccolo M, De Giorgi F, Cho CY, Feng L, Knapp T, Negulescu PA, Taylor SS, Tsien RY, Pozzan T (2000) A genetically encoded, fluorescent indicator for cyclic AMP in living cells. Nat Cell Biol 2:25–29

    Article  PubMed  CAS  Google Scholar 

  • Zaccolo M, Pozzan T (2002) Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science 295:1711–1715

    Article  PubMed  CAS  ADS  Google Scholar 

  • Zhang R, Zhao J, Potter JD (1995) Phosphorylation of both serine residues in cardiac troponin I is required to decrease the Ca2+ affinity of cardiac troponin C. J Biol Chem 270:30773–30780

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by Telethon Italy (TCP00089, GGP05113), the Italian Cystic Fibrosis Research Foundation, the Fondazione Compagnia di San Paolo and the HFSPO (RGP1/2005).

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Authors and Affiliations

  1. Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine, Via Orus 2, 35100, Padova, Italy

    Valentina Lissandron & Manuela Zaccolo

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  1. Valentina Lissandron
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  2. Manuela Zaccolo
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Correspondence to Manuela Zaccolo.

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Lissandron, V., Zaccolo, M. Compartmentalized cAMP/PKA signalling regulates cardiac excitation–contraction coupling. J Muscle Res Cell Motil 27, 399–403 (2006). https://doi.org/10.1007/s10974-006-9077-2

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  • DOI: https://doi.org/10.1007/s10974-006-9077-2

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