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Connexins in the heart

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Abstract

Connexins are essential in the propagation of electrical activity throughout the heart and are an important determinant of conduction velocity. Their dysfunction is an important factor in the genesis of abnormal cardiac rhythm and is relevant to the pathogenesis of a wide variety of cardiac pathologies. Here, we review the basic biology of connexins in the heart but particularly focus on their abnormal function in cardiac disease.

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Abbreviations

ARVC:

Arrhythmogenic right ventricular cardiomyothy

AF:

Atrial fibrillation

Cx43:

Connexin43

NOS1AP:

Nitric oxide synthase-1 adaptor protein

VF:

Ventricular fibrillation

VT:

Ventricular tachycardia

References

  • Aonuma S, Kohama Y, Akai K, Komiyama Y, Nakajima S, Wakabayashi M, Makino T (1980) Studies on heart. XIX. Isolation of an atrial peptide that improves the rhythmicity of cultured myocardial cell clusters. Chem Pharm Bull (Tokyo) 28:3332–3339

    Article  CAS  Google Scholar 

  • Aonuma S, Kohama Y, Makino T, Yoshitake I, Hattori K, Morikawa K, Watanabe Y (1983) Studies on heart. XXIII. Distribution of [1-14C] acetamidino-antiarrhythmic peptide (14C-AAP) in mice. Chem Pharm Bull (Tokyo) 31:612–619

    Article  CAS  Google Scholar 

  • Arking DE, Pfeufer A, Post W, Kao WH, Newton-Cheh C, Ikeda M, West K, Kashuk C, Akyol M, Perz S, Jalilzadeh S, Illig T, Gieger C, Guo CY, Larson MG, Wichmann HE, Marban E, O’Donnell CJ, Hirschhorn JN, Kaab S, Spooner PM, Meitinger T, Chakravarti A (2006) A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet 38:644–651

    Article  CAS  PubMed  Google Scholar 

  • Asimaki A, Kapoor S, Plovie E, Karin AA, Adams E, Liu Z, James CA, Judge DP, Calkins H, Churko J, Wu JC, MacRae CA, Kleber AG, Saffitz JE (2014) Identification of a new modulator of the intercalated disc in a zebrafish model of arrhythmogenic cardiomyopathy. Sci Transl Med 6:240ra74

    Article  PubMed  Google Scholar 

  • Ausma J, Velden HM van der, Lenders MH, Ankeren EP van, Jongsma HJ, Ramaekers FC, Borgers M, Allessie MA (2003) Reverse structural and gap-junctional remodeling after prolonged atrial fibrillation in the goat. Circulation 107:2051–2058

  • Bagwe S, Berenfeld O, Vaidya D, Morley GE, Jalife J (2005) Altered right atrial excitation and propagation in connexin40 knockout mice. Circulation 112:2245–2253

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bakker JM de, Capelle FJ van, Janse MJ, Tasseron S, Vermeulen JT, Jonge N de, Lahpor JR (1993) Slow conduction in the infarcted human heart. “Zigzag” course of activation. Circulation 88:915–926

  • Beardslee MA, Laing JG, Beyer EC, Saffitz JE (1998) Rapid turnover of connexin43 in the adult rat heart. Circ Res 83:629–635

    Article  CAS  PubMed  Google Scholar 

  • Beardslee MA, Lerner DL, Tadros PN, Laing JG, Beyer EC, Yamada KA, Kleber AG, Schuessler RB, Saffitz JE (2000) Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia. Circ Res 87:656–662

    Article  CAS  PubMed  Google Scholar 

  • Beyer EC, Paul DL, Goodenough DA (1987) Connexin43: a protein from rat heart homologous to a gap junction protein from liver. J Cell Biol 105:2621–2629

    Article  CAS  PubMed  Google Scholar 

  • Cerrone M, Noorman M, Lin X, Chkourko H, Liang FX, Nagel R van der, Hund T, Birchmeier W, Mohler P, Veen TA van, Rijen HV van, Delmar M (2012) Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency. Cardiovasc Res 95:460–468

  • Coppen SR, Severs NJ, Gourdie RG (1999) Connexin45 (alpha 6) expression delineates an extended conduction system in the embryonic and mature rodent heart. Dev Genet 24:82–90

    Article  CAS  PubMed  Google Scholar 

  • Danik SB, Liu F, Zhang J, Suk HJ, Morley GE, Fishman GI, Gutstein DE (2004) Modulation of cardiac gap junction expression and arrhythmic susceptibility. Circ Res 95:1035–1041

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Danik SB, Rosner G, Lader J, Gutstein DE, Fishman GI, Morley GE (2008) Electrical remodeling contributes to complex tachyarrhythmias in connexin43-deficient mouse hearts. FASEB J 22:1204–1212

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Davis LM, Kanter HL, Beyer EC, Saffitz JE (1994) Distinct gap junction protein phenotypes in cardiac tissues with disparate conduction properties. J Am Coll Cardiol 24:1124–1132

    Article  CAS  PubMed  Google Scholar 

  • Dekker LR, Fiolet JW, VanBavel E, Coronel R, Opthof T, Spaan JA, Janse MJ (1996) Intracellular Ca2+, intercellular electrical coupling, and mechanical activity in ischemic rabbit papillary muscle. Effects of preconditioning and metabolic blockade. Circ Res 79:237–246

    Article  CAS  PubMed  Google Scholar 

  • Delmar M, McKenna WJ (2010) The cardiac desmosome and arrhythmogenic cardiomyopathies: from gene to disease. Circ Res 107:700–714

    Article  CAS  PubMed  Google Scholar 

  • Derksen R, Rijen HV van, Wilders R, Tasseron S, Hauer RN, Rutten WL, Bakker JM de (2003) Tissue discontinuities affect conduction velocity restitution: a mechanism by which structural barriers may promote wave break. Circulation 108:882–888

  • Dhein S, Manicone N, Muller A, Gerwin R, Ziskoven U, Irankhahi A, Minke C, Klaus W (1994) A new synthetic antiarrhythmic peptide reduces dispersion of epicardial activation recovery interval and diminishes alterations of epicardial activation patterns induced by regional ischemia. a mapping study. Naunyn Schmiedebergs Arch Pharmacol 350:174–184

    Article  CAS  PubMed  Google Scholar 

  • Dhein S, Weng S, Grover R, Tudyka T, Gottwald M, Schaefer T, Polontchouk L (2001) Protein kinase Calpha mediates the effect of antiarrhythmic peptide on gap junction conductance. Cell Commun Adhes 8:257–264

    Article  CAS  PubMed  Google Scholar 

  • Dhein S, Duerrschmidt N, Scholl A, Boldt A, Schulte JS, Pfannmuller B, Rojas-Gomez D, Scheffler A, Haefliger JA, Doll N, Mohr FW (2008) A new role for extracellular Ca2+ in gap-junction remodeling: studies in humans and rats. Naunyn Schmiedebergs Arch Pharmacol 377:125–138

    Article  CAS  PubMed  Google Scholar 

  • Dobrev D, Carlsson L, Nattel S (2012) Novel molecular targets for atrial fibrillation therapy. Nat Rev Drug Discov 11:275–291

    Article  CAS  PubMed  Google Scholar 

  • Dupont E, Ko Y, Rothery S, Coppen SR, Baghai M, Haw M, Severs NJ (2001) The gap-junctional protein connexin40 is elevated in patients susceptible to postoperative atrial fibrillation. Circulation 103:842–849

    Article  CAS  PubMed  Google Scholar 

  • Eckardt D, Theis M, Degen J, Ott T, Rijen HV van, Kirchhoff S, Kim JS, Bakker JM de, Willecke K (2004) Functional role of connexin43 gap junction channels in adult mouse heart assessed by inducible gene deletion. J Mol Cell Cardiol 36:101–110

  • Fialova M, Dlugosova K, Okruhlicova L, Kristek F, Manoach M, Tribulova N (2008) Adaptation of the heart to hypertension is associated with maladaptive gap junction connexin-43 remodeling. Physiol Res 57:7–11

    CAS  PubMed  Google Scholar 

  • Firouzi M, Ramanna H, Kok B, Jongsma HJ, Koeleman BP, Doevendans PA, Groenewegen WA, Hauer RN (2004) Association of human connexin40 gene polymorphisms with atrial vulnerability as a risk factor for idiopathic atrial fibrillation. Circ Res 95:e29–e33

    Article  CAS  PubMed  Google Scholar 

  • Gard JJ, Yamada K, Green KG, Eloff BC, Rosenbaum DS, Wang X, Robbins J, Schuessler RB, Yamada KA, Saffitz JE (2005) Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy. Cardiovasc Res 67:539–547

    Article  CAS  PubMed  Google Scholar 

  • Gollob MH, Jones DL, Krahn AD, Danis L, Gong XQ, Shao Q, Liu X, Veinot JP, Tang AS, Stewart AF, Tesson F, Klein GJ, Yee R, Skanes AC, Guiraudon GM, Ebihara L, Bai D (2006) Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med 354:2677–2688

    Article  CAS  PubMed  Google Scholar 

  • Gomes J, Finlay M, Ahmed AK, Ciaccio EJ, Asimaki A, Saffitz JE, Quarta G, Nobles M, Syrris P, Chaubey S, McKenna WJ, Tinker A, Lambiase PD (2012) Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-A combined murine and human study. Eur Heart J 33:1942–1953

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gourdie RG, Green CR, Severs NJ (1991) Gap junction distribution in adult mammalian myocardium revealed by an anti-peptide antibody and laser scanning confocal microscopy. J Cell Sci 99:41–55

    PubMed  Google Scholar 

  • Groenewegen WA, Firouzi M, Bezzina CR, Vliex S, Langen IM van, Sandkuijl L, Smits JP, Hulsbeek M, Rook MB, Jongsma HJ, Wilde AA (2003) A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill. Circ Res 92:14–22

  • Groot JR de, Coronel R (2004) Acute ischemia-induced gap junctional uncoupling and arrhythmogenesis. Cardiovasc Res 62:323–334

  • Groot JR de, Wilms-Schopman FJ, Opthof T, Remme CA, Coronel R (2001) Late ventricular arrhythmias during acute regional ischemia in the isolated blood perfused pig heart. Role of electrical cellular coupling. Cardiovasc Res 50:362–372

  • Guerrero PA, Schuessler RB, Davis LM, Beyer EC, Johnson CM, Yamada KA, Saffitz JE (1997) Slow ventricular conduction in mice heterozygous for a connexin43 null mutation. J Clin Invest 99:1991–1998

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gutstein DE, Morley GE, Tamaddon H, Vaidya D, Schneider MD, Chen J, Chien KR, Stuhlmann H, Fishman GI (2001) Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res 88:333–339

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gutstein DE, Liu FY, Meyers MB, Choo A, Fishman GI (2003) The organization of adherens junctions and desmosomes at the cardiac intercalated disc is independent of gap junctions. J Cell Sci 116:875–885

    Article  CAS  PubMed  Google Scholar 

  • Hagendorff A, Schumacher B, Kirchhoff S, Luderitz B, Willecke K (1999) Conduction disturbances and increased atrial vulnerability in connexin40-deficient mice analyzed by transesophageal stimulation. Circulation 99:1508–1515

    Article  CAS  PubMed  Google Scholar 

  • Hunter AW, Barker RJ, Zhu C, Gourdie RG (2005) Zonula occludens-1 alters connexin43 gap junction size and organization by influencing channel accretion. Mol Biol Cell 16:5686–5698

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jansen JA, Veen TA van, Bakker JM de, Rijen HV van (2010) Cardiac connexins and impulse propagation. J Mol Cell Cardiol 48:76–82

  • Jansen JA, Noorman M, Musa H, Stein M, Jong S de, Nagel R van der, Hund TJ, Mohler PJ, Vos MA, Veen TA van, Bakker JM de, Delmar M, Rijen HV van (2012) Reduced heterogeneous expression of Cx43 results in decreased Nav1.5 expression and reduced sodium current that accounts for arrhythmia vulnerability in conditional Cx43 knockout mice. Heart Rhythm 9:600–607

  • Jeyaraman M, Tanguy S, Fandrich RR, Lukas A, Kardami E (2003) Ischemia-induced dephosphorylation of cardiomyocyte connexin-43 is reduced by okadaic acid and calyculin A but not fostriecin. Mol Cell Biochem 242:129–134

    Article  CAS  PubMed  Google Scholar 

  • Kaplan SR, Gard JJ, Carvajal-Huerta L, Ruiz-Cabezas JC, Thiene G, Saffitz JE (2004a) Structural and molecular pathology of the heart in Carvajal syndrome. Cardiovasc Pathol 13:26–32

    Article  CAS  PubMed  Google Scholar 

  • Kaplan SR, Gard JJ, Protonotarios N, Tsatsopoulou A, Spiliopoulou C, Anastasakis A, Squarcioni CP, McKenna WJ, Thiene G, Basso C, Brousse N, Fontaine G, Saffitz JE (2004b) Remodeling of myocyte gap junctions in arrhythmogenic right ventricular cardiomyopathy due to a deletion in plakoglobin (Naxos disease). Heart Rhythm 1:3–11

    Article  PubMed  Google Scholar 

  • Kapoor A, Sekar RB, Hansen NF, Fox-Talbot K, Morley M, Pihur V, Chatterjee S, Brandimarto J, Moravec CS, Pulit SL, Pfeufer A, Mullikin J, Ross M, Green ED, Bentley D, Newton-Cheh C, Boerwinkle E, Tomaselli GF, Cappola TP, Arking DE, Halushka MK, Chakravarti A (2014) An enhancer polymorphism at the cardiomyocyte intercalated disc protein NOS1AP locus is a major regulator of the QT interval. Am J Hum Genet 94:854–869

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • King JH, Huang CL, Fraser JA (2013) Determinants of myocardial conduction velocity: implications for arrhythmogenesis. Front Physiol 4:154

    Article  PubMed Central  PubMed  Google Scholar 

  • Kirchhof P, Fabritz L, Zwiener M, Witt H, Schafers M, Zellerhoff S, Paul M, Athai T, Hiller KH, Baba HA, Breithardt G, Ruiz P, Wichter T, Levkau B (2006) Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice. Circulation 114:1799–1806

    Article  PubMed  Google Scholar 

  • Kjolbye AL, Haugan K, Hennan JK, Petersen JS (2007) Pharmacological modulation of gap junction function with the novel compound rotigaptide: a promising new principle for prevention of arrhythmias. Basic Clin Pharmacol Toxicol 101:215–230

    Article  PubMed  Google Scholar 

  • Kleber AG, Janse MJ, Wilms-Schopmann FJ, Wilde AA, Coronel R (1986) Changes in conduction velocity during acute ischemia in ventricular myocardium of the isolated porcine heart. Circulation 73:189–198

    Article  CAS  PubMed  Google Scholar 

  • Kostin S, Klein G, Szalay Z, Hein S, Bauer EP, Schaper J (2002) Structural correlate of atrial fibrillation in human patients. Cardiovasc Res 54:361–379

    Article  CAS  PubMed  Google Scholar 

  • Kreuzberg MM, Sohl G, Kim JS, Verselis VK, Willecke K, Bukauskas FF (2005) Functional properties of mouse connexin30.2 expressed in the conduction system of the heart. Circ Res 96:1169–1177

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kreuzberg MM, Liebermann M, Segschneider S, Dobrowolski R, Dobrzynski H, Kaba R, Rowlinson G, Dupont E, Severs NJ, Willecke K (2009) Human connexin31.9, unlike its orthologous protein connexin30.2 in the mouse, is not detectable in the human cardiac conduction system. J Mol Cell Cardiol 46:553–559

    Article  CAS  PubMed  Google Scholar 

  • Lampe PD, TenBroek EM, Burt JM, Kurata WE, Johnson RG, Lau AF (2000) Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication. J Cell Biol 149:1503–1512

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lampe PD, Cooper CD, King TJ, Burt JM (2006) Analysis of connexin43 phosphorylated at S325, S328 and S330 in normoxic and ischemic heart. J Cell Sci 119:3435–3442

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Laurent G, Leong-Poi H, Mangat I, Moe GW, Hu X, So PP, Tarulli E, Ramadeen A, Rossman EI, Hennan JK, Dorian P (2009) Effects of chronic gap junction conduction-enhancing antiarrhythmic peptide GAP-134 administration on experimental atrial fibrillation in dogs. Circ Arrhythm Electrophysiol 2:171–178

    Article  CAS  PubMed  Google Scholar 

  • Li JY, Lai YJ, Yeh HI, Chen CL, Sun S, Wu SJ, Lin FY (2009) Atrial gap junctions, NF-kappaB and fibrosis in patients undergoing coronary artery bypass surgery: the relationship with postoperative atrial fibrillation. Cardiology 112:81–88

    Article  CAS  PubMed  Google Scholar 

  • Lin R, Warn-Cramer BJ, Kurata WE, Lau AF (2001) v-Src phosphorylation of connexin 43 on Tyr247 and Tyr265 disrupts gap junctional communication. J Cell Biol 154:815–827

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Malhotra JD, Thyagarajan V, Chen C, Isom LL (2004) Tyrosine-phosphorylated and nonphosphorylated sodium channel beta1 subunits are differentially localized in cardiac myocytes. J Biol Chem 279:40748–40754

    Article  CAS  PubMed  Google Scholar 

  • Marquez-Rosado L, Solan JL, Dunn CA, Norris RP, Lampe PD (2012) Connexin43 phosphorylation in brain, cardiac, endothelial and epithelial tissues. Biochim Biophys Acta 1818:1985–1992

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Miragoli M, Gaudesius G, Rohr S (2006) Electrotonic modulation of cardiac impulse conduction by myofibroblasts. Circ Res 98:801–810

    Article  CAS  PubMed  Google Scholar 

  • Miragoli M, Salvarani N, Rohr S (2007) Myofibroblasts induce ectopic activity in cardiac tissue. Circ Res 101:755–758

    CAS  PubMed  Google Scholar 

  • Morley GE, Vaidya D, Jalife J (2000) Characterization of conduction in the ventricles of normal and heterozygous Cx43 knockout mice using optical mapping. J Cardiovasc Electrophysiol 11:375–377

    Article  CAS  PubMed  Google Scholar 

  • Musil LS, Cunningham BA, Edelman GM, Goodenough DA (1990) Differential phosphorylation of the gap junction protein connexin43 in junctional communication-competent and -deficient cell lines. J Cell Biol 111:2077–2088

    Article  CAS  PubMed  Google Scholar 

  • Naitoh K, Yano T, Miura T, Itoh T, Miki T, Tanno M, Sato T, Hotta H, Terashima Y, Shimamoto K (2009) Roles of Cx43-associated protein kinases in suppression of gap junction-mediated chemical coupling by ischemic preconditioning. Am J Physiol Heart Circ Physiol 296:H396–H403

    Article  CAS  PubMed  Google Scholar 

  • Nao T, Ohkusa T, Hisamatsu Y, Inoue N, Matsumoto T, Yamada J, Shimizu A, Yoshiga Y, Yamagata T, Kobayashi S, Yano M, Hamano K, Matsuzaki M (2003) Comparison of expression of connexin in right atrial myocardium in patients with chronic atrial fibrillation versus those in sinus rhythm. Am J Cardiol 91:678–683

    Article  CAS  PubMed  Google Scholar 

  • Nattel S (2002) New ideas about atrial fibrillation 50 years on. Nature 415:219–226

    Article  CAS  PubMed  Google Scholar 

  • O’Quinn MP, Palatinus JA, Harris BS, Hewett KW, Gourdie RG (2011) A peptide mimetic of the connexin43 carboxyl terminus reduces gap junction remodeling and induced arrhythmia following ventricular injury. Circ Res 108:704–715

    Article  PubMed Central  PubMed  Google Scholar 

  • Okruhlicova L, Tribulova N, Misejkova M, Kucka M, Stetka R, Slezak J, Manoach M (2002) Gap junction remodelling is involved in the susceptibility of diabetic rats to hypokalemia-induced ventricular fibrillation. Acta Histochem 104:387–391

    Article  PubMed  Google Scholar 

  • Peters NS, Coromilas J, Severs NJ, Wit AL (1997) Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation 95:988–996

    Article  CAS  PubMed  Google Scholar 

  • Polontchouk L, Haefliger JA, Ebelt B, Schaefer T, Stuhlmann D, Mehlhorn U, Kuhn-Regnier F, De Vivie ER, Dhein S (2001) Effects of chronic atrial fibrillation on gap junction distribution in human and rat atria. J Am Coll Cardiol 38:883–891

    Article  CAS  PubMed  Google Scholar 

  • Quan XQ, Bai R, Lu JG, Patel C, Liu N, Ruan Y, Chen BD, Ruan L, Zhang CT (2009) Pharmacological enhancement of cardiac gap junction coupling prevents arrhythmias in canine LQT2 model. Cell Commun Adhes 16:29–38

    Article  CAS  PubMed  Google Scholar 

  • Reaume AG, De Sousa PA, Kulkarni S, Langille BL, Zhu D, Davies TC, Juneja SC, Kidder GM, Rossant J (1995) Cardiac malformation in neonatal mice lacking connexin43. Science 267:1831–1834

    Article  CAS  PubMed  Google Scholar 

  • Ren Y, Zhang CT, Wu J, Ruan YF, Pu J, He L, Wu W, Chen BD, Wang WG, Wang L (2006) The effects of antiarrhythmic peptide AAP10 on ventricular arrhythmias in rabbits with healed myocardial infarction. Zhonghua Xin Xue Guan Bing Za Zhi 34:825–828

    CAS  PubMed  Google Scholar 

  • Rhett JM, Jourdan J, Gourdie RG (2011) Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1. Mol Biol Cell 22:1516–1528

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rhett JM, Veeraraghavan R, Poelzing S, Gourdie RG (2013) The perinexus: sign-post on the path to a new model of cardiac conduction? Trends Cardiovasc Med 23:222–228

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rijen HV van, Eckardt D, Degen J, Theis M, Ott T, Willecke K, Jongsma HJ, Opthof T, Bakker JM de (2004) Slow conduction and enhanced anisotropy increase the propensity for ventricular tachyarrhythmias in adult mice with induced deletion of connexin43. Circulation 109:1048–1055

  • Rohr S, Kucera JP, Kleber AG (1998) Slow conduction in cardiac tissue. I. Effects of a reduction of excitability versus a reduction of electrical coupling on microconduction. Circ Res 83:781–794

    Article  CAS  PubMed  Google Scholar 

  • Saez JC, Schalper KA, Retamal MA, Orellana JA, Shoji KF, Bennett MV (2010) Cell membrane permeabilization via connexin hemichannels in living and dying cells. Exp Cell Res 316:2377–2389

    Article  CAS  PubMed  Google Scholar 

  • Saffitz JE, Davis LM, Darrow BJ, Kanter HL, Laing JG, Beyer EC (1995) The molecular basis of anisotropy: role of gap junctions. J Cardiovasc Electrophysiol 6:498–510

    Article  CAS  PubMed  Google Scholar 

  • Saiz J, Ferrero JM Jr, Monserrat M, Ferrero JM, Thakor NV (1999) Influence of electrical coupling on early afterdepolarizations in ventricular myocytes. IEEE Trans Biomed Eng 46:138–147

    Article  CAS  PubMed  Google Scholar 

  • Salameh A, Krautblatter S, Karl S, Blanke K, Gomez DR, Dhein S, Pfeiffer D, Janousek J (2009) The signal transduction cascade regulating the expression of the gap junction protein connexin43 by beta-adrenoceptors. Br J Pharmacol 158:198–208

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sato PY, Musa H, Coombs W, Guerrero-Serna G, Patino GA, Taffet SM, Isom LL, Delmar M (2009) Loss of plakophilin-2 expression leads to decreased sodium current and slower conduction velocity in cultured cardiac myocytes. Circ Res 105:523–526

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sato PY, Coombs W, Lin X, Nekrasova O, Green KJ, Isom LL, Taffet SM, Delmar M (2011) Interactions between ankyrin-G, plakophilin-2, and connexin43 at the cardiac intercalated disc. Circ Res 109:193–201

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Scemes E (2012) Nature of plasmalemmal functional “hemichannels”. Biochim Biophys Acta 1818:1880–1883

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shaw RM, Fay AJ, Puthenveedu MA, Zastrow M von, Jan YN, Jan LY (2007) Microtubule plus-end-tracking proteins target gap junctions directly from the cell interior to adherens junctions. Cell 128:547–560

  • Simon AM, Goodenough DA, Paul DL (1998) Mice lacking connexin40 have cardiac conduction abnormalities characteristic of atrioventricular block and bundle branch block. Curr Biol 8:295–298

    Article  CAS  PubMed  Google Scholar 

  • Smith JH, Green CR, Peters NS, Rothery S, Severs NJ (1991) Altered patterns of gap junction distribution in ischemic heart disease. An immunohistochemical study of human myocardium using laser scanning confocal microscopy. Am J Pathol 139:801–821

    PubMed Central  CAS  PubMed  Google Scholar 

  • Smith WT, Fleet WF, Johnson TA, Engle CL, Cascio WE (1995) The Ib phase of ventricular arrhythmias in ischemic in situ porcine heart is related to changes in cell-to-cell electrical coupling. Experimental Cardiology Group, University of North Carolina. Circulation 92:3051–3060

    Article  PubMed  Google Scholar 

  • Smyth JW, Shaw RM (2013) Autoregulation of connexin43 gap junction formation by internally translated isoforms. Cell Rep 5:611–618

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Smyth JW, Hong TT, Gao D, Vogan JM, Jensen BC, Fong TS, Simpson PC, Stainier DY, Chi NC, Shaw RM (2010) Limited forward trafficking of connexin 43 reduces cell-cell coupling in stressed human and mouse myocardium. J Clin Invest 120:266–279

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Smyth JW, Vogan JM, Buch PJ, Zhang SS, Fong TS, Hong TT, Shaw RM (2012) Actin cytoskeleton rest stops regulate anterograde traffic of connexin 43 vesicles to the plasma membrane. Circ Res 110:978–989

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Srisakuldee W, Jeyaraman MM, Nickel BE, Tanguy S, Jiang ZS, Kardami E (2009) Phosphorylation of connexin-43 at serine 262 promotes a cardiac injury-resistant state. Cardiovasc Res 83:672–681

    Article  CAS  PubMed  Google Scholar 

  • Takeuchi S, Akita T, Takagishi Y, Watanabe E, Sasano C, Honjo H, Kodama I (2006) Disorganization of gap junction distribution in dilated atria of patients with chronic atrial fibrillation. Circ J 70:575–582

    Article  PubMed  Google Scholar 

  • The Cardiac Arrhythmia Suppression Trial (CAST) Investigators (1989) Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 321:406–412

    Article  Google Scholar 

  • The Cardiac Arrhythmia Suppression Trial (CAST) Investigators (1992) Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med 327:227–233

    Article  Google Scholar 

  • Thijssen VL, Velden HM van der, Ankeren EP van, Ausma J, Allessie MA, Borgers M, Eys GJ van, Jongsma HJ (2002) Analysis of altered gene expression during sustained atrial fibrillation in the goat. Cardiovasc Res 54:427–437

  • Tribulova N, Okruhlicova L, Imanaga I, Hirosawa N, Ogawa K, Weismann P (2003) Factors involved in the susceptibility of spontaneously hypertensive rats to low K+-induced arrhythmias. Gen Physiol Biophys 22:369–382

    CAS  PubMed  Google Scholar 

  • Velden HM van der, Kempen MJ van, Wijffels MC, Zijverden M van, Groenewegen WA, Allessie MA, Jongsma HJ (1998) Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat. J Cardiovasc Electrophysiol 9:596–607

  • Velden HM van der, Ausma J, Rook MB, Hellemons AJ, Veen TA van, Allessie MA, Jongsma HJ (2000) Gap junctional remodeling in relation to stabilization of atrial fibrillation in the goat. Cardiovasc Res 46:476–486

  • Verheule S, Batenburg CA van, Coenjaerts FE, Kirchhoff S, Willecke K, Jongsma HJ (1999) Cardiac conduction abnormalities in mice lacking the gap junction protein connexin40. J Cardiovasc Electrophysiol 10:1380–1389

  • Viswanathan PC, Rudy Y (2000) Cellular arrhythmogenic effects of congenital and acquired long-QT syndrome in the heterogeneous myocardium. Circulation 101:1192–1198

    Article  CAS  PubMed  Google Scholar 

  • Viswanathan PC, Shaw RM, Rudy Y (1999) Effects of IKr and IKs heterogeneity on action potential duration and its rate dependence: a simulation study. Circulation 99:2466–2474

    Article  CAS  PubMed  Google Scholar 

  • Wang N, De Vuyst E, Ponsaerts R, Boengler K, Palacios-Prado N, Wauman J, Lai CP, De Bock M, Decrock E, Bol M, Vinken M, Rogiers V, Tavernier J, Evans WH, Naus CC, Bukauskas FF, Sipido KR, Heusch G, Schulz R, Bultynck G, Leybaert L (2013) Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury. Basic Res Cardiol 108:309

    Article  PubMed Central  PubMed  Google Scholar 

  • Wetzel U, Boldt A, Lauschke J, Weigl J, Schirdewahn P, Dorszewski A, Doll N, Hindricks G, Dhein S, Kottkamp H (2005) Expression of connexins 40 and 43 in human left atrium in atrial fibrillation of different aetiologies. Heart 91:166–170

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wilhelm M, Kirste W, Kuly S, Amann K, Neuhuber W, Weyand M, Daniel WG, Garlichs C (2006) Atrial distribution of connexin 40 and 43 in patients with intermittent, persistent, and postoperative atrial fibrillation. Heart Lung Circ 15:30–37

    Article  CAS  PubMed  Google Scholar 

  • Xie Y, Garfinkel A, Camelliti P, Kohl P, Weiss JN, Qu Z (2009) Effects of fibroblast-myocyte coupling on cardiac conduction and vulnerability to reentry: a computational study. Heart Rhythm 6:1641–1649

    Article  PubMed Central  PubMed  Google Scholar 

  • Xing D, Kjolbye AL, Nielsen MS, Petersen JS, Harlow KW, Holstein-Rathlou NH, Martins JB (2003) ZP123 increases gap junctional conductance and prevents reentrant ventricular tachycardia during myocardial ischemia in open chest dogs. J Cardiovasc Electrophysiol 14:510–520

    Article  PubMed  Google Scholar 

  • Yan GX, Kleber AG (1992) Changes in extracellular and intracellular pH in ischemic rabbit papillary muscle. Circ Res 71:460–470

    Article  CAS  PubMed  Google Scholar 

  • Zicha J, Pechanova O, Cacanyiova S, Cebova M, Kristek F, Torok J, Simko F, Dobesova Z, Kunes J (2006) Hereditary hypertriglyceridemic rat: a suitable model of cardiovascular disease and metabolic syndrome? Physiol Res 55(Suppl 1):S49–S63

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institute of Cardiovascular Science, Heart Hospital, UCL, 16-18 Westmoreland Street, London, W1G 8PH, UK

    Pier D. Lambiase

  2. William Harvey Heart Centre, Barts & The London School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK

    Andrew Tinker

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  1. Pier D. Lambiase
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  2. Andrew Tinker
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Correspondence to Andrew Tinker.

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The work in the authors’ laboratories is or has been supported by the British Heart Foundation, Medical Research Council, Wellcome Trust, The National Institute for Health Research Barts Cardiovascular Biomedical Research Unit, UCLH Biomedicine NIHR and Heart Research UK.

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Lambiase, P.D., Tinker, A. Connexins in the heart. Cell Tissue Res 360, 675–684 (2015). https://doi.org/10.1007/s00441-014-2020-8

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  • DOI: https://doi.org/10.1007/s00441-014-2020-8

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