Abstract
Compartmentalization of signaling enzymes allows cardiomyocytes to make contextually specific decisions using a common set of second messengers. Though first identified by their role in localizing the pleiotropic cAMP-dependent protein kinase A (PKA) to specific intracellular organelles and compartments, A-kinase-anchoring proteins (AKAPs) are a structurally and functionally diverse family of multivalent scaffolds that organize “signalosomes” constituting critical nodes in the cell-type-specific network of intracellular signaling pathways. This chapter summarizes the role of AKAPs in cardiomyocytes, with a focus on the intersection of compartmentalized signaling and cardiac pathophysiology.
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References
Abrenica B, AlShaaban M, Czubryt MP (2009) The A-kinase anchor protein AKAP121 is a negative regulator of cardiomyocyte hypertrophy. J Mol Cell Cardiol 46:674–681
Appert-Collin A, Cotecchia S, Nenniger-Tosato M et al (2007) The A-kinase anchoring protein (AKAP)-Lbc-signaling complex mediates α1 adrenergic receptor-induced cardiomyocyte hypertrophy. Proc Natl Acad Sci 104:10140–10145. doi:10.1073/pnas.0701099104
Bartos DC, Grandi E, Ripplinger CM (2015) Ion channels in the heart. Compr Physiol 5:1423–1464. doi:10.1002/cphy.c140069
Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415:198–205. doi:10.1038/415198a
Bers DM (2008) Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol 70:23–49. doi:10.1146/annurev.physiol.70.113006.100455
Bidwell P, Blackwell DJ, Hou Z et al (2011) Phospholamban binds with differential affinity to calcium pump conformers. J Biol Chem 286:35044–35050. doi:10.1074/jbc.M111.266759
Bodi I, Mikala G, Koch SE et al (2005) The L-type calcium channel in the heart: the beat goes on. J Clin Invest 115(12):3306–3317. doi:10.1172/JCI27167
Cariolato L, Cavin S, Diviani D (2011) A-kinase anchoring protein (AKAP)-Lbc anchors a PKN-based signaling complex involved in α1-adrenergic receptor-induced p38 activation. J Biol Chem 286:7925–7937. doi:10.1074/jbc.M110.185645
Carnegie GK, Soughayer J, Smith FD et al (2008) AKAP-Lbc mobilizes a cardiac hypertrophy signaling pathway. Mol Cell 32:169–179. doi:10.1016/j.molcel.2008.08.030
Champion HC (2005) Targeting protein phosphatase 1 in heart failure. Circ Res 96:708–710. doi:10.1161/01.RES.0000164359.95588.25
Chen L, Kass RS (2006) Dual roles of the A kinase-anchoring protein Yotiao in the modulation of a cardiac potassium channel: a passive adaptor versus an active regulator. Eur J Cell Biol 85:623–626. doi:10.1016/j.ejcb.2006.03.002
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. doi:10.1074/jbc.M505191200
Chen L, Marquardt ML, Tester DJ et al (2007) Mutation of an A-kinase-anchoring protein causes long-QT syndrome. Proc Natl Acad Sci U S A 104:20990–20995. doi:10.1073/pnas.0710527105
Cohn JN, Ferrari R, Sharpe N, Forum I (2000) Cardiac remodeling—concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll Cardiol 35(3):569–582
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. doi:10.1074/jbc.M106629200
Diviani D, Dodge-Kafka KL, Li J, Kapiloff MS (2011) A-kinase anchoring proteins: scaffolding proteins in the heart. AJP Hear Circ Physiol 301:H1742–H1753. doi:10.1152/ajpheart.00569.2011
Diviani D, Maric D, Perez Lopez I et al (2013) A-kinase anchoring proteins: molecular regulators of the cardiac stress response. Biochim Biophys Acta 1833:901–908. doi:10.1016/j.bbamcr.2012.07.014
Dodge-Kafka KL, Soughayer J, Pare GC et al (2005) The protein kinase a anchoring protein mAKAP coordinates two integrated cAMP effector pathways. Nature 437:574–578. doi:10.1038/nature03966
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. doi:10.1161/01.RES.0000218273.91741.30
Durham JT, Brand OM, Arnold M et al (2006) Myospryn is a direct transcriptional target for MEF2A that encodes a striated muscle, alpha-actinin-interacting, costamere-localized protein. J Biol Chem 281:6841–6849. doi:10.1074/jbc.M510499200
Edwards HV, Scott JD, Baillie GS (2012) The A-kinase-anchoring protein AKAP-lbc facilitates cardioprotective PKA phosphorylation of Hsp20 on Ser(16). Biochem J 446:437–443. doi:10.1042/BJ20120570
Fink MA, Zakhary DR, Mackey JA et al (2001) AKAP-mediated targeting of protein kinase a regulates contractility in cardiac myocytes. Circ Res 88:291–297
Fraser LDC, Tavalin SJ, Lester LB et al (1998) A novel lipid-anchored A-kinase anchoring protein facilitates cAMP-responsive membrane events. EMBO J 17:2261–2272. doi:10.1093/emboj/17.8.2261
Frey N, Katus HA, Olson EN, Hill JA (2004) Hypertrophy of the heart: a new therapeutic target? Circulation 109:1580–1589. doi:10.1161/01.CIR.0000120390.68287.BB
Gray PC, Johnson BD, Westenbroek RE et al (1998) Primary structure and function of an a kinase anchoring protein associated with calcium channels. Neuron 20:1017–1026. doi:10.1016/S0896-6273(00)80482-1
Greenwald EC, Redden JM, Dodge-Kafka KL, Saucerman JJ (2013) Scaffold state-switching amplifies, accelerates and insulates protein kinase C signaling. J Biol Chem 289(4):2353–2360. doi:10.1074/jbc.M113.497941
Grimby G, Nilsson NJ, Saltin B (1966) Cardiac output during submaximal and maximal exercise in active middle-aged athletes. J Appl Physiol 21:1150–1156
Grossman W, Jones D, McLaurin LP (1975) Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 56:56–64. doi:10.1172/JCI108079
Guillory AN, Yin X, Wijaya CS et al (2013) Enhanced cardiac function in Gravin mutant mice involves alterations in the β-adrenergic receptor signaling cascade. PLoS One 8:e74784. doi:10.1371/journal.pone.0074784
Hall DD, Davare MA, Shi 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 46:1635–1646. doi:10.1021/bi062217x
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
Hill JA, Olson EN (2008) Cardiac plasticity. N Engl J Med 358:1370–1380. doi:10.1056/NEJMra072139
Hoffmann R, Baillie GS, MacKenzie SJ et al (1999) The MAP kinase ERK2 inhibits the cyclic AMP-specific phosphodiesterase HSPDE4D3 by phosphorylating it at Ser579. EMBO J 18:893–903
Hulme JT, Ahn M, Hauschka SD et al (2002) A novel leucine zipper targets AKAP15 and cyclic AMP-dependent protein kinase to the C terminus of the skeletal muscle Ca2+ channel and modulates its function. J Biol Chem 277:4079–4087. doi:10.1074/jbc.M109814200
Jones BW, Brunet S, Gilbert ML et al (2012) Cardiomyocytes from AKAP7 knockout mice respond normally to adrenergic stimulation. Proc Natl Acad Sci U S A 109:17099–17104. doi:10.1073/pnas.1215219109
Kamp TJ, Hell JW (2000) Regulation of cardiac L-type calcium channels by protein kinase A and protein kinase C. Circ Res 87:1095–1102. doi:10.1161/01.RES.87.12.1095
Kapiloff MS, Schillace RV, Westphal AM, Scott JD (1999) mAKAP: an A-kinase anchoring protein targeted to the nuclear membrane of differentiated myocytes. J Cell Sci 112(Pt 1):2725–2736
Kapiloff MS, Piggott LA, Sadana R et al (2009) An adenylyl cyclase-mAKAPbeta signaling complex regulates cAMP levels in cardiac myocytes. J Biol Chem 284:23540–23546. doi:10.1074/jbc.M109.030072
Katz AM (2008) The “modern” view of heart failure: how did we get here? Circ Heart Fail 1:63–71. doi:10.1161/CIRCHEARTFAILURE.108.772756
Katz AM, Lorell BH (2000) Regulation of cardiac contraction and relaxation. Circulation 102:Iv-69–Iv-74
Keely SL, Corbin JD (1977) Involvement of cAMP-dependent protein kinase in the regulation of heart contractile force. Am J Physiol Heart Circ Physiol 233:H269–H275
Kritzer MD, Li J, Dodge-Kafka K, Kapiloff MS (2012) AKAPs: the architectural underpinnings of local cAMP signaling. J Mol Cell Cardiol 52:351–358
Kritzer MD, Li J, Passariello CL et al (2014) The scaffold protein muscle A-kinase anchoring protein beta orchestrates cardiac myocyte hypertrophic signaling required for the development of heart failure. Circ Heart Fail 7:663–672. doi:10.1161/CIRCHEARTFAILURE.114.001266
Levy MN (1971) Brief reviews: sympathetic-parasympathetic interactions in the heart. Circ Res 29:437–445. doi:10.1161/01.RES.29.5.437
Li J, Negro A, Lopez J et al (2010) The mAKAPbeta scaffold regulates cardiac myocyte hypertrophy via recruitment of activated calcineurin. J Mol Cell Cardiol 48:387–394. doi:10.1016/j.yjmcc.2009.10.023
Li Y, Chen L, Kass RS, Dessauer CW (2012) The A-kinase anchoring protein Yotiao facilitates complex formation between adenylyl cyclase type 9 and the IKs potassium channel in heart. J Biol Chem 287:29815–29824. doi:10.1074/jbc.M112.380568
Li J, Kritzer MD, Michel JJC et al (2013a) Anchored p90 ribosomal S6 kinase 3 is required for cardiac myocyte hypertrophy. Circ Res 112:128–139. doi:10.1161/CIRCRESAHA.112.276162
Li J, Vargas MAX, Kapiloff MS, Dodge-Kafka KL (2013b) Regulation of MEF2 transcriptional activity by calcineurin/mAKAP complexes. Exp Cell Res 319:447–454. doi:10.1016/j.yexcr.2012.12.016
Lin C, Guo X, Lange S et al (2013) Cypher/ZASP is a novel A-kinase anchoring protein. J Biol Chem 288:29403–29413. doi:10.1074/jbc.M113.470708
Lygren B, Carlson CR, Santamaria K et al (2007) AKAP complex regulates Ca2+ re-uptake into heart sarcoplasmic reticulum. EMBO Rep 8:1061–1067. doi:10.1038/sj.embor.7401081
Lymperopoulos A, Rengo G, Koch WJ (2013) Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ Res 113:739–753. doi:10.1161/CIRCRESAHA.113.300308
McCartney S, Little BM, Langeberg LK, Scott JD (1995) Cloning and characterization of A-kinase anchor protein 100 (AKAP100). A protein that targets A-kinase to the sarcoplasmic reticulum. J Biol Chem 270:9327–9333
McConnell BK, Popovic Z, Mai N et al (2009) Disruption of protein kinase a interaction with A-kinase-anchoring proteins in the heart in vivo effects on cardiac contractility, protein kinase a phosphorylation, and troponin i proteolysis. J Biol Chem 284:1583–1592. doi:10.1074/jbc.M806321200
McConnell B, Suryavanshi S, Fa’ak F et al (2016) Disruption of Gravin’s Scaffolding protects against isoproterenol induced heart failure. FASEB J 30:718.6–718.6
Molkentin JD (2004) Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovasc Res 63:467–475. doi:10.1016/j.cardiores.2004.01.021
Mozaffarian D, Benjamin EJ, Go AS et al (2015) Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation 133(4):e38–360
Nag AC (1980) Study of non-muscle cells of the adult mammalian heart: a fine structural analysis and distribution. Cytobios 28:41–61
Newlon MG, Roy M, Morikis D et al (1999) The molecular basis for protein kinase A anchoring revealed by solution NMR. Nat Struct Biol 6:222–227. doi:10.1038/6663
Nichols CB, Rossow CF, Navedo MF et al (2010) Sympathetic stimulation of adult cardiomyocytes requires association of AKAP5 with a subpopulation of L-type calcium channels. Circ Res 107:747–756. doi:10.1161/CIRCRESAHA.109.216127
Nicolaou P, Hajjar RJ, Kranias EG (2009) Role of protein phosphatase-1 inhibitor-1 in cardiac physiology and pathophysiology. J Mol Cell Cardiol 47:365–371
Pare GC, Bauman AL, McHenry M et al (2005) The mAKAP complex participates in the induction of cardiac myocyte hypertrophy by adrenergic receptor signaling. J Cell Sci 118:5637–5646. doi:10.1242/jcs.02675
Passariello CL, Li J, Dodge-Kafka K, Kapiloff MS (2015) mAKAP-a master scaffold for cardiac remodeling. J Cardiovasc Pharmacol 65:218–225. doi:10.1097/FJC.0000000000000206
Pérez López I, Cariolato L, Maric D et al (2013) A-kinase anchoring protein Lbc coordinates a p38 activating signaling complex controlling compensatory cardiac hypertrophy. Mol Cell Biol 33:2903–2917. doi:10.1128/MCB.00031-13
Perino A, Ghigo A, Ferrero E et al (2011) Integrating cardiac PIP3 and cAMP signaling through a PKA anchoring function of p110γ. Mol Cell 42:84–95. doi:10.1016/j.molcel.2011.01.030
Perrino C, Feliciello A, Schiattarella GG et al (2010) AKAP121 downregulation impairs protective cAMP signals, promotes mitochondrial dysfunction, and increases oxidative stress. Cardiovasc Res 88:101–110. doi:10.1093/cvr/cvq155
Potthoff MJ, Olson EN (2007) MEF2: a central regulator of diverse developmental programs. Development 134:4131–4140. doi:10.1242/dev.008367
Redden JM, Dodge-Kafka KL (2011) AKAP phosphatase complexes in the heart. J Cardiovasc Pharmacol 58:354–362
Redden JM, Le AV, Singh A et al (2012) Spatiotemporal regulation of PKC via interactions with AKAP7 isoforms. Biochem J 446:301–309
Remme WJ, Swedberg K (2001) Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 22:1527–1560. doi:10.1053/euhj.2001.2783
Reynolds JG, McCalmon SA, Tomczyk T, Naya FJ (2007) Identification and mapping of protein kinase A binding sites in the costameric protein myospryn. Biochim Biophys Acta 1773:891–902. doi:10.1016/j.bbamcr.2007.04.004
Reynolds JG, McCalmon SA, Donaghey JA, Naya FJ (2008) Deregulated protein kinase A signaling and myospryn expression in muscular dystrophy. J Biol Chem 283:8070–8074. doi:10.1074/jbc.C700221200
Rigatti M, Le AV, Gerber C et al (2015) Phosphorylation state-dependent interaction between AKAP7δ/γ and phospholamban increases phospholamban phosphorylation. Cell Signal 27:1807–1815. doi:10.1016/j.cellsig.2015.05.016
Romeo Y, Zhang X, Roux PP (2012) Regulation and function of the RSK family of protein kinases. Biochem J 441:553–569. doi:10.1042/BJ20110289
Russell MA, Lund LM, Haber R et al (2006) The intermediate filament protein, synemin, is an AKAP in the heart. Arch Biochem Biophys 456:204–215. doi:10.1016/j.abb.2006.06.010
Satin J (2013) The long and short of PKC modulation of the L-type calcium channel. Channels 7:57–58. doi:10.4161/chan.24147
Sciarretta S, Volpe M, Sadoshima J (2014) Mammalian target of rapamycin signaling in cardiac physiology and disease. Circ Res 114:549–564. doi:10.1161/CIRCRESAHA.114.302022
Scott JD, Santana LF (2010) A-kinase anchoring proteins: getting to the heart of the matter. Circulation 121:1264–1271. doi:10.1161/CIRCULATIONAHA.109.896357
Shanks MO, Lund LM, Manni S et al (2012) Chromodomain helicase binding protein 8 (Chd8) is a novel A-kinase anchoring protein expressed during rat cardiac development. PLoS One 7:e46316. doi:10.1371/journal.pone.0046316
Shih M, Lin F, Scott JD et al (1999) Dynamic complexes of beta2-adrenergic receptors with protein kinases and phosphatases and the role of gravin. J Biol Chem 274:1588–1595
Simmerman HK, Jones LR (1998) Phospholamban: protein structure, mechanism of action, and role in cardiac function. Physiol Rev 78:921–947
Singh A, Redden JMJ, Kapiloff MSM, Dodge-Kafka KL (2011) The large isoforms of AKAP18 mediate the phosphorylation of inhibitor-1 by PKA and the inhibition of PP1 activity. Mol Pharmacol 79:533–540. doi:10.1124/mol.110.065425
Singh A, Rigatti M, Le AV et al (2015) Analysis of AKAP7γ dimerization. J Signal Transduct 2015:371626. doi:10.1155/2015/371626
Spragg DD, Leclercq C, Loghmani M et al (2003) Regional alterations in protein expression in the dyssynchronous failing heart. Circulation 108:929–932. doi:10.1161/01.CIR.0000088782.99568.CA
Strakova J, Dean JD, Sharpe KM et al (2014) Dystrobrevin increases dystrophin’s binding to the dystrophin-glycoprotein complex and provides protection during cardiac stress. J Mol Cell Cardiol 76:106–115. doi:10.1016/j.yjmcc.2014.08.013
Sumandea CA, Garcia-Cazarin ML, Bozio CH et al (2011) Cardiac troponin T, a sarcomeric AKAP, tethers protein kinase A at the myofilaments. J Biol Chem 286:530–541. doi:10.1074/jbc.M110.148684
Taglieri DM, Johnson KR, Burmeister BT et al (2014) The C-terminus of the long AKAP13 isoform (AKAP-Lbc) is critical for development of compensatory cardiac hypertrophy. J Mol Cell Cardiol 66:27–40. doi:10.1016/j.yjmcc.2013.10.010
Terrenoire C, Clancy CE, Cormier JW et al (2005) Autonomic control of cardiac action potentials: role of potassium channel kinetics in response to sympathetic stimulation. Circ Res 96:e25–e34. doi:10.1161/01.RES.0000160555.58046.9a
Terrenoire C, Houslay MD, Baillie GS, Kass RS (2009) The cardiac IKs potassium channel macromolecular complex includes the phosphodiesterase PDE4D3. J Biol Chem 284:9140–9146. doi:10.1074/jbc.M805366200
Tingley WG, Pawlikowska L, Zaroff JG et al (2007) Gene-trapped mouse embryonic stem cell-derived cardiac myocytes and human genetics implicate AKAP10 in heart rhythm regulation. Proc Natl Acad Sci U S A 104:8461–8466. doi:10.1073/pnas.0610393104
Trotter KW, Fraser IDC, Scott GK et al (1999) Alternative splicing regulates the subcellular localization of A-kinase anchoring protein 18 isoforms. J Cell Biol 147:1481–1492. doi:10.1083/jcb.147.7.1481
Uys GM, Ramburan A, Loos B et al (2011) Myomegalin is a novel A-kinase anchoring protein involved in the phosphorylation of cardiac myosin binding protein C. BMC Cell Biol 12:18. doi:10.1186/1471-2121-12-18
Vargas MAX, Tirnauer JS, Glidden N et al (2012) Myocyte enhancer factor 2 (MEF2) tethering to muscle selective A-kinase anchoring protein (mAKAP) is necessary for myogenic differentiation. Cell Signal 24:1496–1503. doi:10.1016/j.cellsig.2012.03.017
Viquerat CE, Daly P, Swedberg K et al (1985) Endogenous catecholamine levels in chronic heart failure. Relation to the severity of hemodynamic abnormalities. Am J Med 78:455–460. doi:10.1016/0002-9343(85)90338-9
Wong W, Scott JD (2004) AKAP signalling complexes: focal points in space and time. Nat Rev Mol Cell Biol 5:959–970. doi:10.1038/nrm1527
World Health Organization (2005) Preventing chronic diseases. A vital investment: WHO global report. World Health Organization, Geneva
Zhang L, Malik S, Kelley GG et al (2011) Phospholipase C epsilon scaffolds to muscle-specific A kinase anchoring protein (mAKAPbeta) and integrates multiple hypertrophic stimuli in cardiac myocytes. J Biol Chem 286:23012–23021. doi:10.1074/jbc.M111.231993
Zhang L, Malik S, Pang J et al (2013) Phospholipase Cε hydrolyzes perinuclear phosphatidylinositol 4-phosphate to regulate cardiac hypertrophy. Cell 153:216–227. doi:10.1016/j.cell.2013.02.047
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This work was funded by the State of Connecticut Department of Public Health Grant 2014-0133 (K.D.K.) and the US National Institutes of Health Grants HL126825 (K.D.K. and M.S.K.) and HL075398 (M.S.K.)
Conflict of Interest Statement
Drs. Kapiloff and Dodge-Kafka are coinventors of patented intellectual property concerning the use of RSK3 and AKAP6 inhibitors for the treatment of heart failure and by which they and the University of Miami may gain royalties from future commercialization. Dr. Kapiloff is the manager of Anchored RSK3 Inhibitors, LLC, and president of Cardiac RSK3 Inhibitors, LLC, companies interested in developing RSK3-targeted therapies and in which Dr. Kapiloff holds equity.
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Redden, J.M., Dodge-Kafka, K.L., Kapiloff, M.S. (2017). Function to Failure: Compartmentalization of Cardiomyocyte Signaling by A-Kinase-Anchoring Proteins. In: Nikolaev, V., Zaccolo, M. (eds) Microdomains in the Cardiovascular System. Cardiac and Vascular Biology, vol 3. Springer, Cham. https://doi.org/10.1007/978-3-319-54579-0_3
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