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Intercalated discs: cellular adhesion and signaling in heart health and diseases

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Abstract

Intercalated discs (ICDs) are highly orchestrated structures that connect neighboring cardiomyocytes in the heart. Three major complexes are distinguished in ICD: desmosome, adherens junction (AJ), and gap junction (GJ). Desmosomes are major cell adhesion junctions that anchor cell membrane to the intermediate filament network; AJs connect the actin cytoskeleton of adjacent cells; and gap junctions metabolically and electrically connect the cytoplasm of adjacent cardiomyocytes. All these complexes work as a single unit, the so-called area composita, interdependently rather than individually. Mutation or altered expression of ICD proteins results in various cardiac diseases, such as ARVC (arrhythmogenic right ventricular cardiomyopathy), dilated cardiomyopathy, and hypotrophy cardiomyopathy, eventually leading to heart failure. In this article, we first review the recent findings on the structural organization of ICD and their functions and then focus on the recent advances in molecular pathogenesis of the ICD-related heart diseases, which include two major areas: i) the ICD gene mutations in cardiac diseases, and ii) the involvement of ICD proteins in signal transduction pathways leading to myocardium remodeling and eventual heart failure. These major ICD-related signaling pathways include Wnt/β-catenin pathway, p38 MAPK cascade, Rho-dependent serum response factor (SRF) signaling, calcineurin/NFAT signaling, Hippo kinase cascade, etc., which are differentially regulated in pathological conditions.

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References

  1. Sheikh F, Ross RS, Chen J (2009) Cell-cell connection to cardiac disease. Trends Cardiovasc Med 19(6):182–190

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Vermij SH, Abriel H, van Veen TA (2017) Refining the molecular organization of the cardiac intercalated disc. Cardiovasc Res 113(3):259–275

    CAS  PubMed  Google Scholar 

  3. van Hengel J, Calore M, Bauce B, Dazzo E, Mazzotti E, De Bortoli M, Lorenzon A, Li Mura IE, Beffagna G, Rigato I, Vleeschouwers M, Tyberghein K, Hulpiau P, van Hamme E, Zaglia T, Corrado D, Basso C, Thiene G, Daliento L, Nava A, van Roy F, Rampazzo A (2013) Mutations in the area composita protein alphaT-catenin are associated with arrhythmogenic right ventricular cardiomyopathy. Eur Heart J 34(3):201–210

    PubMed  Google Scholar 

  4. Swope D, Cheng L, Gao E, Li J, Radice GL (2012) Loss of cadherin-binding proteins beta-catenin and plakoglobin in the heart leads to gap junction remodeling and arrhythmogenesis. Mol Cell Biol 32(6):1056–1067

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Vite A, Li J, Radice GL (2015) New functions for alpha-catenins in health and disease: from cancer to heart regeneration. Cell Tissue Res 360(3):773–783

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hatzfeld M, Wolf A, Keil R (2014) Plakophilins in desmosomal adhesion and signaling. Cell Commun Adhes 21(1):25–42

    CAS  PubMed  Google Scholar 

  7. Johnson JL, Najor NA, Green KJ (2014) Desmosomes: regulators of cellular signaling and adhesion in epidermal health and disease. Cold Spring Harb Perspect Med 4(11):a015297

    PubMed  PubMed Central  Google Scholar 

  8. Rubsam M, Broussard JA, Wickstrom SA, Nekrasova O, Green KJ, Niessen CM (2017) Adherens junctions and desmosomes coordinate mechanics and signaling to orchestrate tissue morphogenesis and function: an evolutionary perspective. Cold Spring Harb Perspect Biol. https://doi.org/10.1101/cshperspect.a029207

  9. Manring HR, Dorn LE, Ex-Willey A, Accornero F, Ackermann MA (2018) At the heart of inter- and intracellular signaling: the intercalated disc. Biophys Rev 10(4):961–971

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Hutz K, Zeiler J, Sachs L, Ormanns S, Spindler V (2017) Loss of desmoglein 2 promotes tumorigenic behavior in pancreatic cancer cells. Mol Carcinog 56(8):1884–1895

    PubMed  Google Scholar 

  11. Garrod D, Chidgey M (2008) Desmosome structure, composition and function. Biochim Biophys Acta 1778(3):572–587

    CAS  PubMed  Google Scholar 

  12. Dusek RL, Godsel LM, Green KJ (2007) Discriminating roles of desmosomal cadherins: beyond desmosomal adhesion. J Dermatol Sci 45(1):7–21

    CAS  PubMed  Google Scholar 

  13. Garrod DR, Merritt AJ, Nie Z (2002) Desmosomal adhesion: structural basis, molecular mechanism and regulation (review). Mol Membr Biol 19(2):81–94

    CAS  PubMed  Google Scholar 

  14. Hatzfeld M (2005) The p120 family of cell adhesion molecules. Eur J Cell Biol 84(2–3):205–214

    CAS  PubMed  Google Scholar 

  15. Hatzfeld M (2007) Plakophilins: multifunctional proteins or just regulators of desmosomal adhesion? Biochim Biophys Acta 1773(1):69–77

    CAS  PubMed  Google Scholar 

  16. Ackermann MA, Hu L-YR, Kontrogianni-Konstantopoulos A (2012) Intercellular connections in the heart: the intercalated disc. In: Veselka J (ed) Cardiomyopathies - From Basic Research to Clinical Management. InTech, pp 245–276

  17. Choi HJ, Gross JC, Pokutta S, Weis WI (2009) Interactions of plakoglobin and beta-catenin with desmosomal cadherins: basis of selective exclusion of alpha- and beta-catenin from desmosomes. J Biol Chem 284(46):31776–31788

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Hofmann I, Mertens C, Brettel M, Nimmrich V, Schnolzer M, Herrmann H (2000) Interaction of plakophilins with desmoplakin and intermediate filament proteins: an in vitro analysis. J Cell Sci 113(Pt 13):2471–2483

    CAS  PubMed  Google Scholar 

  19. 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(2):193–201

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Holthofer B, Windoffer R, Troyanovsky S, Leube RE (2007) Structure and function of desmosomes. Int Rev Cytol 264:65–163

    PubMed  Google Scholar 

  21. Noorman M, van der Heyden MA, van Veen TA, Cox MG, Hauer RN, de Bakker JM, van Rijen HV (2009) Cardiac cell-cell junctions in health and disease: electrical versus mechanical coupling. J Mol Cell Cardiol 47(1):23–31

    CAS  PubMed  Google Scholar 

  22. Delmar M, McKenna WJ (2010) The cardiac desmosome and arrhythmogenic cardiomyopathies: from gene to disease. Circ Res 107(6):700–714

    CAS  PubMed  Google Scholar 

  23. Seeger TS, Frank D, Rohr C, Will R, Just S, Grund C, Lyon R, Luedde M, Koegl M, Sheikh F, Rottbauer W, Franke WW, Katus HA, Olson EN, Frey N (2010) Myozap, a novel intercalated disc protein, activates serum response factor-dependent signaling and is required to maintain cardiac function in vivo. Circ Res 106(5):880–890

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Frank D, Rangrez AY, Poyanmehr R, Seeger TS, Kuhn C, Eden M, Stiebeling K, Bernt A, Grund C, Franke WW, Frey N (2014) Mice with cardiac-restricted overexpression of myozap are sensitized to biomechanical stress and develop a protein-aggregate-associated cardiomyopathy. J Mol Cell Cardiol 72:196–207

    CAS  PubMed  Google Scholar 

  25. Wang Q, Lin JL, Wu KH, Wang DZ, Reiter RS, Sinn HW, Lin CI, Lin CJ (2012) Xin proteins and intercalated disc maturation, signaling and diseases. Front Biosci (Landmark Ed) 17:2566–2593

    Google Scholar 

  26. Bays JL, Peng X, Tolbert CE, Guilluy C, Angell AE, Pan Y, Superfine R, Burridge K, DeMali KA (2014) Vinculin phosphorylation differentially regulates mechanotransduction at cell-cell and cell-matrix adhesions. J Cell Biol 205(2):251–263

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Vite A, Radice GL (2014) N-cadherin/catenin complex as a master regulator of intercalated disc function. Cell Commun Adhes 21(3):169–179

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kaufmann U, Zuppinger C, Waibler Z, Rudiger M, Urbich C, Martin B, Jockusch BM, Eppenberger H, Starzinski-Powitz A (2000) The armadillo repeat region targets ARVCF to cadherin-based cellular junctions. J Cell Sci 113(Pt 22):4121–4135

    CAS  PubMed  Google Scholar 

  29. Ye X, Zhang HM, Qiu Y, Hanson PJ, Hemida MG, Wei W, Hoodless PA, Chu F, Yang D (2014) Coxsackievirus-induced miR-21 disrupts cardiomyocyte interactions via the downregulation of intercalated disk components. PLoS Pathog 10(4):e1004070

    PubMed  PubMed Central  Google Scholar 

  30. Janssens B, Goossens S, Staes K, Gilbert B, van Hengel J, Colpaert C, Bruyneel E, Mareel M, van Roy F (2001) alphaT-catenin: a novel tissue-specific beta-catenin-binding protein mediating strong cell-cell adhesion. J Cell Sci 114(Pt 17):3177–3188

    CAS  PubMed  Google Scholar 

  31. Goossens S, Janssens B, Bonne S, De Rycke R, Braet F, van Hengel J, van Roy F (2007) A unique and specific interaction between alphaT-catenin and plakophilin-2 in the area composita, the mixed-type junctional structure of cardiac intercalated discs. J Cell Sci 120(Pt 12):2126–2136

    CAS  PubMed  Google Scholar 

  32. Talhouk RS, Mroue R, Mokalled M, Abi-Mosleh L, Nehme R, Ismail A, Khalil A, Zaatari M, El-Sabban ME (2008) Heterocellular interaction enhances recruitment of alpha and beta-catenins and ZO-2 into functional gap-junction complexes and induces gap junction-dependant differentiation of mammary epithelial cells. Exp Cell Res 314(18):3275–3291

    CAS  PubMed  Google Scholar 

  33. Choi S, Gustafson-Wagner EA, Wang Q, Harlan SM, Sinn HW, Lin JL, Lin JJ (2007) The intercalated disk protein, mXinalpha, is capable of interacting with beta-catenin and bundling actin filaments [corrected]. J Biol Chem 282(49):36024–36036

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Schroen B, Leenders JJ, van Erk A, Bertrand AT, van Loon M, van Leeuwen RE, Kubben N, Duisters RF, Schellings MW, Janssen BJ, Debets JJ, Schwake M, Hoydal MA, Heymans S, Saftig P, Pinto YM (2007) Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy. J Exp Med 204(5):1227–1235

    CAS  PubMed  PubMed Central  Google Scholar 

  35. BioGrid3.4 Homo sapiens. in Tylerslab.com, ed.(2015)

  36. Bennett PM, Maggs AM, Baines AJ, Pinder JC (2006) The transitional junction: a new functional subcellular domain at the intercalated disc. Mol Biol Cell 17(4):2091–2100

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Zong L, Zhu Y, Liang R, Zhao HB (2016) Gap junction mediated miRNA intercellular transfer and gene regulation: a novel mechanism for intercellular genetic communication. Sci Rep 6:19884

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Bernstein SA, Morley GE (2006) Gap junctions and propagation of the cardiac action potential. Adv Cardiol 42:71–85

    CAS  PubMed  Google Scholar 

  39. Sohl G, Willecke K (2004) Gap junctions and the connexin protein family. Cardiovasc Res 62(2):228–232

    PubMed  Google Scholar 

  40. Severs NJ, Bruce AF, Dupont E, Rothery S (2008) Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res 80(1):9–19

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 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(12):5686–5698

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Rhett JM, Jourdan J, Gourdie RG (2011) Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1. Mol Biol Cell 22(9):1516–1528

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Liu L, Li Y, Lin J, Liang Q, Sheng X, Wu J, Huang R, Liu S, Li Y (2010) Connexin 43 interacts with caveolin-3 in the heart. Mol Biol Rep 37(4):1685–1691

    CAS  PubMed  Google Scholar 

  44. Giepmans BN, Verlaan I, Moolenaar WH (2001) Connexin-43 interactions with ZO-1 and alpha- and beta-tubulin. Cell Commun Adhes 8(4–6):219–223

    CAS  PubMed  Google Scholar 

  45. 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(1):266–279

    CAS  PubMed  Google Scholar 

  46. Benz PM, Merkel CJ, Offner K, Abesser M, Ullrich M, Fischer T, Bayer B, Wagner H, Gambaryan S, Ursitti JA, Adham IM, Linke WA, Feller SM, Fleming I, Renne T, Frantz S, Unger A, Schuh K (2013) Mena/VASP and alphaII-spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy. Cell Commun Signal 11:56

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ram R, Wescott AP, Varandas K, Dirksen RT, Blaxall BC (2014) Mena associates with Rac1 and modulates connexin 43 remodeling in cardiomyocytes. Am J Physiol Heart Circ Physiol 306(1):H154–H159

    CAS  PubMed  Google Scholar 

  48. Basso C, Bauce B, Corrado D, Thiene G (2011) Pathophysiology of arrhythmogenic cardiomyopathy. Nat Rev Cardiol 9(4):223–233

    PubMed  Google Scholar 

  49. Rampazzo A, Calore M, van Hengel J, van Roy F (2014) Intercalated discs and arrhythmogenic cardiomyopathy. Circ Cardiovasc Genet 7(6):930–940

    PubMed  Google Scholar 

  50. Marcus FI, Edson S, Towbin JA (2013) Genetics of arrhythmogenic right ventricular cardiomyopathy: a practical guide for physicians. J Am Coll Cardiol 61(19):1945–1948

    PubMed  Google Scholar 

  51. Broussard JA, Getsios S, Green KJ (2015) Desmosome regulation and signaling in disease. Cell Tissue Res 360(3):501–512

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Najor NA (2018) Desmosomes in human disease. Annu Rev Pathol 13:51–70

    CAS  PubMed  Google Scholar 

  53. Calore M, Lorenzon A, De Bortoli M, Poloni G, Rampazzo A (2015) Arrhythmogenic cardiomyopathy: a disease of intercalated discs. Cell Tissue Res 360(3):491–500

    CAS  PubMed  Google Scholar 

  54. Hall CL, Sutanto H, Dalageorgou C, McKenna WJ, Syrris P, Futema M (2018) Frequency of genetic variants associated with arrhythmogenic right ventricular cardiomyopathy in the genome aggregation database. Eur J Hum Genet 26(9):1312–1318

    CAS  PubMed  PubMed Central  Google Scholar 

  55. van der Zwaag PA, Jongbloed JD, van den Berg MP, van der Smagt JJ, Jongbloed R, Bikker H, Hofstra RM, van Tintelen JP (2009) A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy. Hum Mutat 30(9):1278–1283

    PubMed  Google Scholar 

  56. Lorenzon A, Pilichou K, Rigato I, Vazza G, De Bortoli M, Calore M, Occhi G, Carturan E, Lazzarini E, Cason M, Mazzotti E, Poloni G, Mostacciuolo ML, Daliento L, Thiene G, Corrado D, Basso C, Bauce B, Rampazzo A (2015) Homozygous desmocollin-2 mutations and arrhythmogenic cardiomyopathy. Am J Cardiol 116(8):1245–1251

    CAS  PubMed  Google Scholar 

  57. Pilichou K, Lazzarini E, Rigato I, Celeghin R, De Bortoli M, Perazzolo Marra M, Cason M, Jongbloed J, Calore M, Rizzo S, Regazzo D, Poloni G, Iliceto S, Daliento L, Delise P, Corrado D, Van Tintelen JP, Thiene G, Rampazzo A, Basso C, Bauce B, Lorenzon A, Occhi G (2017) Large genomic rearrangements of desmosomal genes in Italian arrhythmogenic cardiomyopathy patients. Circ Arrhythm Electrophysiol 10 (10)

  58. Awad MM, Dalal D, Cho E, Amat-Alarcon N, James C, Tichnell C, Tucker A, Russell SD, Bluemke DA, Dietz HC, Calkins H, Judge DP (2006) DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am J Hum Genet 79(1):136–142

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhou X, Chen M, Song H, Wang B, Chen H, Wang J, Wang W, Feng S, Zhang F, Ju W, Li M, Gu K, Cao K, Wang DW, Yang B (2015) Comprehensive analysis of desmosomal gene mutations in Han Chinese patients with arrhythmogenic right ventricular cardiomyopathy. Eur J Med Genet 58(4):258–265

    PubMed  Google Scholar 

  60. Liu JS, Fan LL, Li JJ, Xiang R (2017) Whole-exome sequencing identifies a novel mutation of desmocollin 2 in a Chinese family with arrhythmogenic right ventricular cardiomyopathy. Am J Cardiol 119(9):1485–1489

    CAS  PubMed  Google Scholar 

  61. Zhang M, Xue A, Shen Y, Oliveira JB, Li L, Zhao Z, Burke A (2015) Mutations of desmoglein-2 in sudden death from arrhythmogenic right ventricular cardiomyopathy and sudden unexplained death. Forensic Sci Int 255:85–88

    CAS  PubMed  Google Scholar 

  62. Pereira Fernandes M, Azevedo O, Pereira V, Calvo L, Lourenco A (2015) Arrhythmogenic right ventricular cardiomyopathy with left ventricular involvement: a novel splice site mutation in the DSG2 gene. Cardiology 130(3):159–161

    CAS  PubMed  Google Scholar 

  63. Lin Y, Zhang Q, Zhong ZA, Xu Z, He S, Rao F, Liu Y, Tang J, Wang F, Liu H, Xie J, Wu H, Wang S, Li X, Shan Z, Deng C, Liao Z, Deng H, Liao H, Xue Y, Chen W, Zhan X, Zhang B, Wu S (2017) Whole genome sequence identified a rare homozygous pathogenic mutation of the DSG2 gene in a familial arrhythmogenic cardiomyopathy involving both ventricles. Cardiology 138(1):41–54

    PubMed  Google Scholar 

  64. Qadri S, Anttonen O, Viikila J, Seppala EH, Myllykangas S, Alastalo TP, Holmstrom M, Helio T, Koskenvuo JW (2017) Case reports of two pedigrees with recessive arrhythmogenic right ventricular cardiomyopathy associated with homozygous Thr335Ala variant in DSG2. BMC Med Genet 18(1):86

    PubMed  PubMed Central  Google Scholar 

  65. Finsterer J, Stollberger C, Wollmann E, Dertinger S, Laccone F (2016) Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe). Mol Genet Metab Rep 8:1–3

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Bitar F, Najjar T, Hayashi R, Nemer G, Shigehara Y, Hamie L, Abbas O, Kibbi AG, Shimomura Y, Kurban M (2016) A novel heterozygous mutation in desmoplakin gene in a Lebanese patient with Carvajal syndrome and tooth agenesis. J Eur Acad Dermatol Venereol 30(12):e217–e219

    CAS  PubMed  Google Scholar 

  67. Foss-Nieradko B, Franaszczyk M, Spiewak M, Oreziak A, Ploski R, Bilinska ZT (2016) Novel truncating desmoplakin mutation as a potential cause of sudden cardiac death in a family. Pol Arch Med Wewn 126(9):704–707

    PubMed  Google Scholar 

  68. Docekal JW, Lee JC (2017) Novel gene mutation identified in a patient with arrhythmogenic ventricular cardiomyopathy. HeartRhythm Case Rep 3(10):459–463

    PubMed  PubMed Central  Google Scholar 

  69. Trenkwalder T, Deisenhofer I, Hadamitzky M, Schunkert H, Reinhard W (2015) Novel frame-shift mutation in PKP2 associated with arrhythmogenic right ventricular cardiomyopathy: a case report. BMC Med Genet 16:117

    PubMed  PubMed Central  Google Scholar 

  70. Soveizi M, Rabbani B, Rezaei Y, Saedi S, Najafi N, Maleki M, Mahdieh N (2017) Autosomal recessive nonsyndromic arrhythmogenic right ventricular cardiomyopathy without cutaneous involvements: a novel mutation. Ann Hum Genet 81(4):135–140

    CAS  PubMed  Google Scholar 

  71. Mahdieh N, Saedi S, Soveizi M, Rabbani B, Najafi N, Maleki M (2018) A novel PKP2 mutation and intrafamilial phenotypic variability in ARVC/D. Med J Islam Repub Iran 32:5

    PubMed  PubMed Central  Google Scholar 

  72. Mayosi BM, Fish M, Shaboodien G, Mastantuono E, Kraus S, Wieland T, Kotta MC, Chin A, Laing N, Ntusi NB, Chong M, Horsfall C, Pimstone SN, Gentilini D, Parati G, Strom TM, Meitinger T, Pare G, Schwartz PJ, Crotti L (2017) Identification of cadherin 2 (CDH2) mutations in arrhythmogenic right ventricular cardiomyopathy. Circ Cardiovasc Genet 10 (2)

  73. Turkowski KL, Tester DJ, Bos JM, Haugaa KH, Ackerman MJ (2017) Whole exome sequencing with genomic triangulation implicates CDH2-encoded N-cadherin as a novel pathogenic substrate for arrhythmogenic cardiomyopathy. Congenit Heart Dis 12(2):226–235

    PubMed  Google Scholar 

  74. Wu Q, Wu Y, Zhang L, Zheng J, Tang S, Cheng J (2017) GJA1 gene variations in sudden unexplained nocturnal death syndrome in the Chinese Han population. Forensic Sci Int 270:178–182

    CAS  PubMed  Google Scholar 

  75. Sen-Chowdhry S, Morgan RD, Chambers JC, McKenna WJ (2010) Arrhythmogenic cardiomyopathy: etiology, diagnosis, and treatment. Annu Rev Med 61:233–253

    CAS  PubMed  Google Scholar 

  76. van Tintelen JP, Hofstra RM, Wiesfeld AC, van den Berg MP, Hauer RN, Jongbloed JD (2007) Molecular genetics of arrhythmogenic right ventricular cardiomyopathy: emerging horizon? Curr Opin Cardiol 22(3):185–192

    PubMed  Google Scholar 

  77. Fressart V, Duthoit G, Donal E, Probst V, Deharo JC, Chevalier P, Klug D, Dubourg O, Delacretaz E, Cosnay P, Scanu P, Extramiana F, Keller D, Hidden-Lucet F, Simon F, Bessirard V, Roux-Buisson N, Hebert JL, Azarine A, Casset-Senon D, Rouzet F, Lecarpentier Y, Fontaine G, Coirault C, Frank R, Hainque B, Charron P (2010) Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice. Europace 12(6):861–868

    PubMed  Google Scholar 

  78. Wada Y, Ohno S, Aiba T, Horie M (2017) Unique genetic background and outcome of non-Caucasian Japanese probands with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Mol Genet Genomic Med 5(6):639–651

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Simpson MA, Mansour S, Ahnood D, Kalidas K, Patton MA, McKenna WJ, Behr ER, Crosby AH (2009) Homozygous mutation of desmocollin-2 in arrhythmogenic right ventricular cardiomyopathy with mild palmoplantar keratoderma and woolly hair. Cardiology 113(1):28–34

    CAS  PubMed  Google Scholar 

  80. Syrris P, Ward D, Evans A, Asimaki A, Gandjbakhch E, Sen-Chowdhry S, McKenna WJ (2006) Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2. Am J Hum Genet 79(5):978–984

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Posch MG, Posch MJ, Geier C, Erdmann B, Mueller W, Richter A, Ruppert V, Pankuweit S, Maisch B, Perrot A, Buttgereit J, Dietz R, Haverkamp W, Ozcelik C (2008) A missense variant in desmoglein-2 predisposes to dilated cardiomyopathy. Mol Genet Metab 95(1–2):74–80

    CAS  PubMed  Google Scholar 

  82. Lombardi R, Marian AJ (2011) Molecular genetics and pathogenesis of arrhythmogenic right ventricular cardiomyopathy: a disease of cardiac stem cells. Pediatr Cardiol 32(3):360–365

    PubMed  Google Scholar 

  83. Pilichou K, Nava A, Basso C, Beffagna G, Bauce B, Lorenzon A, Frigo G, Vettori A, Valente M, Towbin J, Thiene G, Danieli GA, Rampazzo A (2006) Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 113(9):1171–1179

    CAS  PubMed  Google Scholar 

  84. Kirchner F, Schuetz A, Boldt LH, Martens K, Dittmar G, Haverkamp W, Thierfelder L, Heinemann U, Gerull B (2012) Molecular insights into arrhythmogenic right ventricular cardiomyopathy caused by plakophilin-2 missense mutations. Circ Cardiovasc Genet 5(4):400–411

    CAS  PubMed  Google Scholar 

  85. Rasmussen TB, Nissen PH, Palmfeldt J, Gehmlich K, Dalager S, Jensen UB, Kim WY, Heickendorff L, Molgaard H, Jensen HK, Baandrup UT, Bross P, Mogensen J (2014) Truncating plakophilin-2 mutations in arrhythmogenic cardiomyopathy are associated with protein haploinsufficiency in both myocardium and epidermis. Circ Cardiovasc Genet 7(3):230–240

    CAS  PubMed  Google Scholar 

  86. Xia X, Batra N, Shi Q, Bonewald LF, Sprague E, Jiang JX (2010) Prostaglandin promotion of osteocyte gap junction function through transcriptional regulation of connexin 43 by glycogen synthase kinase 3/beta-catenin signaling. Mol Cell Biol 30(1):206–219

    CAS  PubMed  Google Scholar 

  87. Chen J, Nekrasova OE, Patel DM, Klessner JL, Godsel LM, Koetsier JL, Amargo EV, Desai BV, Green KJ (2012) The C-terminal unique region of desmoglein 2 inhibits its internalization via tail-tail interactions. J Cell Biol 199(4):699–711

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Gehmlich K, Asimaki A, Cahill TJ, Ehler E, Syrris P, Zachara E, Re F, Avella A, Monserrat L, Saffitz JE, McKenna WJ (2010) Novel missense mutations in exon 15 of desmoglein-2: role of the intracellular cadherin segment in arrhythmogenic right ventricular cardiomyopathy? Heart Rhythm 7(10):1446–1453

    PubMed  PubMed Central  Google Scholar 

  89. Gehmlich K, Syrris P, Reimann M, Asimaki A, Ehler E, Evans A, Quarta G, Pantazis A, Saffitz JE, McKenna WJ (2012) Molecular changes in the heart of a severe case of arrhythmogenic right ventricular cardiomyopathy caused by a desmoglein-2 null allele. Cardiovasc Pathol 21(4):275–282

    CAS  PubMed  Google Scholar 

  90. Zhang M, Lu S, Wu X, Chen Y, Song X, Jin Z, Li H, Zhou Y, Chen F, Huo Y (2012) Multimarker approach for the prediction of cardiovascular events in patients with mild to moderate coronary artery lesions. A 3-year follow-up study. Int Heart J 53(2):85–90

    CAS  PubMed  Google Scholar 

  91. Beffagna G, De Bortoli M, Nava A, Salamon M, Lorenzon A, Zaccolo M, Mancuso L, Sigalotti L, Bauce B, Occhi G, Basso C, Lanfranchi G, Towbin JA, Thiene G, Danieli GA, Rampazzo A (2007) Missense mutations in desmocollin-2 N-terminus, associated with arrhythmogenic right ventricular cardiomyopathy, affect intracellular localization of desmocollin-2 in vitro. BMC Med Genet 8:65

    PubMed  PubMed Central  Google Scholar 

  92. 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 (2004) Remodeling of myocyte gap junctions in arrhythmogenic right ventricular cardiomyopathy due to a deletion in plakoglobin (Naxos disease). Heart Rhythm 1(1):3–11

    PubMed  Google Scholar 

  93. Asimaki A, Syrris P, Wichter T, Matthias P, Saffitz JE, McKenna WJ (2007) A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 81(5):964–973

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Chalabreysse L, Senni F, Bruyere P, Aime B, Ollagnier C, Bozio A, Bouvagnet P (2011) A new hypo/oligodontia syndrome: Carvajal/Naxos syndrome secondary to desmoplakin-dominant mutations. J Dent Res 90(1):58–64

    CAS  PubMed  Google Scholar 

  95. Keller DI, Stepowski D, Balmer C, Simon F, Guenthard J, Bauer F, Itin P, David N, Drouin-Garraud V, Fressart V (2012) De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease. Swiss Med Wkly 142:w13670

    PubMed  Google Scholar 

  96. Norgett EE, Hatsell SJ, Carvajal-Huerta L, Cabezas JC, Common J, Purkis PE, Whittock N, Leigh IM, Stevens HP, Kelsell DP (2000) Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet 9(18):2761–2766

    CAS  PubMed  Google Scholar 

  97. Haas J, Frese KS, Peil B, Kloos W, Keller A, Nietsch R, Feng Z, Muller S, Kayvanpour E, Vogel B, Sedaghat-Hamedani F, Lim WK, Zhao X, Fradkin D, Kohler D, Fischer S, Franke J, Marquart S, Barb I, Li DT, Amr A, Ehlermann P, Mereles D, Weis T, Hassel S, Kremer A, King V, Wirsz E, Isnard R, Komajda M, Serio A, Grasso M, Syrris P, Wicks E, Plagnol V, Lopes L, Gadgaard T, Eiskjaer H, Jorgensen M, Garcia-Giustiniani D, Ortiz-Genga M, Crespo-Leiro MG, Deprez RH, Christiaans I, van Rijsingen IA, Wilde AA, Waldenstrom A, Bolognesi M, Bellazzi R, Morner S, Bermejo JL, Monserrat L, Villard E, Mogensen J, Pinto YM, Charron P, Elliott P, Arbustini E, Katus HA, Meder B (2015) Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J 36(18):1123–1135a

    CAS  PubMed  Google Scholar 

  98. Li J, Patel VV, Radice GL (2006) Dysregulation of cell adhesion proteins and cardiac arrhythmogenesis. Clin Med Res 4(1):42–52

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Li J, Patel VV, Kostetskii I, Xiong Y, Chu AF, Jacobson JT, Yu C, Morley GE, Molkentin JD, Radice GL (2005) Cardiac-specific loss of N-cadherin leads to alteration in connexins with conduction slowing and arrhythmogenesis. Circ Res 97(5):474–481

    CAS  PubMed  Google Scholar 

  100. Kostetskii I, Li J, Xiong Y, Zhou R, Ferrari VA, Patel VV, Molkentin JD, Radice GL (2005) Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure. Circ Res 96(3):346–354

    CAS  PubMed  Google Scholar 

  101. Janssens B, Mohapatra B, Vatta M, Goossens S, Vanpoucke G, Kools P, Montoye T, van Hengel J, Bowles NE, van Roy F, Towbin JA (2003) Assessment of the CTNNA3 gene encoding human alpha T-catenin regarding its involvement in dilated cardiomyopathy. Hum Genet 112(3):227–236

    CAS  PubMed  Google Scholar 

  102. Zemljic-Harpf AE, Miller JC, Henderson SA, Wright AT, Manso AM, Elsherif L, Dalton ND, Thor AK, Perkins GA, McCulloch AD, Ross RS (2007) Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Mol Cell Biol 27(21):7522–7537

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Vasile VC, Will ML, Ommen SR, Edwards WD, Olson TM, Ackerman MJ (2006) Identification of a metavinculin missense mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy. Mol Genet Metab 87(2):169–174

    CAS  PubMed  Google Scholar 

  104. Lim BK, Xiong D, Dorner A, Youn TJ, Yung A, Liu TI, Gu Y, Dalton ND, Wright AT, Evans SM, Chen J, Peterson KL, McCulloch AD, Yajima T, Knowlton KU (2008) Coxsackievirus and adenovirus receptor (CAR) mediates atrioventricular-node function and connexin 45 localization in the murine heart. J Clin Invest 118(8):2758–2770

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Kaur T, Mishra B, Saikia UN, Sharma M, Bahl A, Ratho RK (2012) Expression of coxsackievirus and adenovirus receptor and its cellular localization in myocardial tissues of dilated cardiomyopathy. Exp Clin Cardiol 17(4):183–186

    PubMed  PubMed Central  Google Scholar 

  106. Dobrowolski R, Willecke K (2009) Connexin-caused genetic diseases and corresponding mouse models. Antioxid Redox Signal 11(2):283–295

    CAS  PubMed  Google Scholar 

  107. Kelly SC, Ratajczak P, Keller M, Purcell SM, Griffin T, Richard G (2006) A novel GJA 1 mutation in oculo-dento-digital dysplasia with curly hair and hyperkeratosis. Eur J Dermatol 16(3):241–245

    PubMed  Google Scholar 

  108. Manias JL, Plante I, Gong XQ, Shao Q, Churko J, Bai D, Laird DW (2008) Fate of connexin43 in cardiac tissue harbouring a disease-linked connexin43 mutant. Cardiovasc Res 80(3):385–395

    CAS  PubMed  Google Scholar 

  109. Prevedel L, Morocho C, Bennett MVL, Eugenin EA (2017) HIV-associated cardiovascular disease: role of connexin 43. Am J Pathol 187(9):1960–1970

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Kostin S, Dammer S, Hein S, Klovekorn WP, Bauer EP, Schaper J (2004) Connexin 43 expression and distribution in compensated and decompensated cardiac hypertrophy in patients with aortic stenosis. Cardiovasc Res 62(2):426–436

    CAS  PubMed  Google Scholar 

  111. Michela P, Velia V, Aldo P, Ada P (2015) Role of connexin 43 in cardiovascular diseases. Eur J Pharmacol 768:71–76

    CAS  PubMed  Google Scholar 

  112. Xu HF, Ding YJ, Shen YW, Xue AM, Xu HM, Luo CL, Li BX, Liu YL, Zhao ZQ (2012) MicroRNA- 1 represses Cx43 expression in viral myocarditis. Mol Cell Biochem 362(1–2):141–148

    CAS  PubMed  Google Scholar 

  113. Inose H, Ochi H, Kimura A, Fujita K, Xu R, Sato S, Iwasaki M, Sunamura S, Takeuchi Y, Fukumoto S, Saito K, Nakamura T, Siomi H, Ito H, Arai Y, Shinomiya K, Takeda S (2009) A microRNA regulatory mechanism of osteoblast differentiation. Proc Natl Acad Sci U S A 106(49):20794–20799

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Katsuno T, Umeda K, Matsui T, Hata M, Tamura A, Itoh M, Takeuchi K, Fujimori T, Nabeshima Y, Noda T, Tsukita S, Tsukita S (2008) Deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells. Mol Biol Cell 19(6):2465–2475

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Kudo-Sakamoto Y, Akazawa H, Ito K, Takano J, Yano M, Yabumoto C, Naito AT, Oka T, Lee JK, Sakata Y, Suzuki J, Saido TC, Komuro I (2014) Calpain-dependent cleavage of N-cadherin is involved in the progression of post-myocardial infarction remodeling. J Biol Chem 289(28):19408–19419

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Ando K, Uemura K, Kuzuya A, Maesako M, Asada-Utsugi M, Kubota M, Aoyagi N, Yoshioka K, Okawa K, Inoue H, Kawamata J, Shimohama S, Arai T, Takahashi R, Kinoshita A (2011) N-cadherin regulates p38 MAPK signaling via association with JNK-associated leucine zipper protein: implications for neurodegeneration in Alzheimer disease. J Biol Chem 286(9):7619–7628

    CAS  PubMed  Google Scholar 

  117. Rangrez AY, Eden M, Poyanmehr R, Kuhn C, Stiebeling K, Dierck F, Bernt A, Lullmann-Rauch R, Weiler H, Kirchof P, Frank D, Frey N (2016) Myozap deficiency promotes adverse cardiac remodeling via differential regulation of mitogen-activated protein kinase/serum-response factor and beta-catenin/GSK-3beta protein signaling. J Biol Chem 291(8):4128–4143

    CAS  PubMed  Google Scholar 

  118. Li J, Swope D, Raess N, Cheng L, Muller EJ, Radice GL (2011) Cardiac tissue-restricted deletion of plakoglobin results in progressive cardiomyopathy and activation of {beta}-catenin signaling. Mol Cell Biol 31(6):1134–1144

    PubMed  PubMed Central  Google Scholar 

  119. Lymperopoulos A, Rengo G, Koch WJ (2013) Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ Res 113(6):739–753

    CAS  PubMed  Google Scholar 

  120. Schlipp A, Schinner C, Spindler V, Vielmuth F, Gehmlich K, Syrris P, McKenna WJ, Dendorfer A, Hartlieb E, Waschke J (2014) Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function. Cardiovasc Res 104(2):245–257

    CAS  PubMed  Google Scholar 

  121. Schinner C, Vielmuth F, Rotzer V, Hiermaier M, Radeva MY, Co TK, Hartlieb E, Schmidt A, Imhof A, Messoudi A, Horn A, Schlipp A, Spindler V, Waschke J (2017) Adrenergic signaling strengthens cardiac myocyte cohesion. Circ Res 120(8):1305–1317

    CAS  PubMed  Google Scholar 

  122. Kamekura R, Kolegraff KN, Nava P, Hilgarth RS, Feng M, Parkos CA, Nusrat A (2014) Loss of the desmosomal cadherin desmoglein-2 suppresses colon cancer cell proliferation through EGFR signaling. Oncogene 33(36):4531–4536

    CAS  PubMed  Google Scholar 

  123. Tokonzaba E, Chen J, Cheng X, Den Z, Ganeshan R, Muller EJ, Koch PJ (2013) Plakoglobin as a regulator of desmocollin gene expression. J Invest Dermatol 133(12):2732–2740

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Kolegraff K, Nava P, Helms MN, Parkos CA, Nusrat A (2011) Loss of desmocollin-2 confers a tumorigenic phenotype to colonic epithelial cells through activation of Akt/beta-catenin signaling. Mol Biol Cell 22(8):1121–1134

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Fang WK, Liao LD, Li LY, Xie YM, Xu XE, Zhao WJ, Wu JY, Zhu MX, Wu ZY, Du ZP, Wu BL, Xie D, Guo MZ, Xu LY, Li EM (2013) Down-regulated desmocollin-2 promotes cell aggressiveness through redistributing adherens junctions and activating beta-catenin signalling in oesophageal squamous cell carcinoma. J Pathol 231(2):257–270

    CAS  PubMed  Google Scholar 

  126. Li D, Liu Y, Maruyama M, Zhu W, Chen H, Zhang W, Reuter S, Lin SF, Haneline LS, Field LJ, Chen PS, Shou W (2011) Restrictive loss of plakoglobin in cardiomyocytes leads to arrhythmogenic cardiomyopathy. Hum Mol Genet 20(23):4582–4596

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Spindler V, Dehner C, Hubner S, Waschke J (2014) Plakoglobin but not desmoplakin regulates keratinocyte cohesion via modulation of p38MAPK signaling. J Invest Dermatol 134(6):1655–1664

    CAS  PubMed  Google Scholar 

  128. Chen SN, Gurha P, Lombardi R, Ruggiero A, Willerson JT, Marian AJ (2014) The hippo pathway is activated and is a causal mechanism for adipogenesis in arrhythmogenic cardiomyopathy. Circ Res 114(3):454–468

    CAS  PubMed  Google Scholar 

  129. Khudiakov AA, Kostina DA, Kostareva AA, Tomilin AN, Malashicheva AB (2015) The effect of plakophilin-2 gene mutations on activity of the canonical Wnt signaling pathway. Tsitologiia 57(12):868–875

    CAS  PubMed  Google Scholar 

  130. Godsel LM, Dubash AD, Bass-Zubek AE, Amargo EV, Klessner JL, Hobbs RP, Chen X, Green KJ (2010) Plakophilin 2 couples actomyosin remodeling to desmosomal plaque assembly via RhoA. Mol Biol Cell 21(16):2844–2859

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Arimoto K, Burkart C, Yan M, Ran D, Weng S, Zhang DE (2014) Plakophilin-2 promotes tumor development by enhancing ligand-dependent and -independent epidermal growth factor receptor dimerization and activation. Mol Cell Biol 34(20):3843–3854

    PubMed  PubMed Central  Google Scholar 

  132. Leitner L, Shaposhnikov D, Mengel A, Descot A, Julien S, Hoffmann R, Posern G (2011) MAL/MRTF-A controls migration of non-invasive cells by upregulation of cytoskeleton-associated proteins. J Cell Sci 124(Pt 24):4318–4331

    CAS  PubMed  Google Scholar 

  133. Garcia-Gras E, Lombardi R, Giocondo MJ, Willerson JT, Schneider MD, Khoury DS, Marian AJ (2006) Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Invest 116(7):2012–2021

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Chen X, Bonne S, Hatzfeld M, van Roy F, Green KJ (2002) Protein binding and functional characterization of plakophilin 2. Evidence for its diverse roles in desmosomes and beta-catenin signaling. J Biol Chem 277(12):10512–10522

    CAS  PubMed  Google Scholar 

  135. Patel DM, Dubash AD, Kreitzer G, Green KJ (2014) Disease mutations in desmoplakin inhibit Cx43 membrane targeting mediated by desmoplakin-EB1 interactions. J Cell Biol 206(6):779–797

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Cabral RM, Tattersall D, Patel V, McPhail GD, Hatzimasoura E, Abrams DJ, South AP, Kelsell DP (2012) The DSPII splice variant is crucial for desmosome-mediated adhesion in HaCaT keratinocytes. J Cell Sci 125(Pt 12):2853–2861

    CAS  PubMed  Google Scholar 

  137. Li J, Gao E, Vite A, Yi R, Gomez L, Goossens S, van Roy F, Radice GL (2015) Alpha-catenins control cardiomyocyte proliferation by regulating yap activity. Circ Res 116(1):70–79

    CAS  PubMed  Google Scholar 

  138. Bergmann MW (2010) Wnt signaling in adult cardiac hypertrophy and remodeling: lessons learned from cardiac development. Circ Res 107(10):1198–1208

    CAS  PubMed  Google Scholar 

  139. Dunach M, Del Valle-Perez B, Garcia de Herreros A (2017) p120-catenin in canonical Wnt signaling. Crit Rev Biochem Mol Biol 52(3):327–339

    CAS  PubMed  Google Scholar 

  140. Solan JL, Lampe PD (2016) Kinase programs spatiotemporally regulate gap junction assembly and disassembly: effects on wound repair. Semin Cell Dev Biol 50:40–48

    CAS  PubMed  Google Scholar 

  141. Ek-Vitorin JF, King TJ, Heyman NS, Lampe PD, Burt JM (2006) Selectivity of connexin 43 channels is regulated through protein kinase C-dependent phosphorylation. Circ Res 98(12):1498–1505

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Ishikawa S, Kuno A, Tanno M, Miki T, Kouzu H, Itoh T, Sato T, Sunaga D, Murase H, Miura T (2012) Role of connexin-43 in protective PI3K-Akt-GSK-3 beta signaling in cardiomyocytes. Am J Physiol Heart Circ Physiol 302(12):H2536–H2544

    CAS  PubMed  Google Scholar 

  143. Dunn CA, Lampe PD (2014) Injury-triggered Akt phosphorylation of Cx43: a ZO-1-driven molecular switch that regulates gap junction size. J Cell Sci 127(Pt 2):455–464

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Coyne CB, Bergelson JM (2006) Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions. Cell 124(1):119–131

    CAS  PubMed  Google Scholar 

  145. Farmer C, Morton PE, Snippe M, Santis G, Parsons M (2009) Coxsackie adenovirus receptor (CAR) regulates integrin function through activation of p44/42 MAPK. Exp Cell Res 315(15):2637–2647

    CAS  PubMed  Google Scholar 

  146. Caruso L, Yuen S, Smith J, Husain M, Opavsky MA (2010) Cardiomyocyte-targeted overexpression of the coxsackie-adenovirus receptor causes a cardiomyopathy in association with beta-catenin signaling. J Mol Cell Cardiol 48(6):1194–1205

    CAS  PubMed  Google Scholar 

  147. Grossmann KS, Grund C, Huelsken J, Behrend M, Erdmann B, Franke WW, Birchmeier W (2004) Requirement of plakophilin 2 for heart morphogenesis and cardiac junction formation. J Cell Biol 167(1):149–160

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Kowalczyk AP, Green KJ (2013) Structure, function, and regulation of desmosomes. Prog Mol Biol Transl Sci 116:95–118

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Sun Y, Zhang J, Ma L (2014) Alpha-catenin. A tumor suppressor beyond adherens junctions. Cell Cycle 13(15):2334–2339

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Kim W, Kim M, Jho EH (2013) Wnt/beta-catenin signalling: from plasma membrane to nucleus. Biochem J 450(1):9–21

    CAS  PubMed  Google Scholar 

  151. Anastas JN (2015) Functional crosstalk between Wnt signaling and tyrosine kinase signaling in cancer. Semin Oncol 42(6):820–831

    CAS  PubMed  Google Scholar 

  152. Sadot E, Simcha I, Iwai K, Ciechanover A, Geiger B, Ben-Ze’ev A (2000) Differential interaction of plakoglobin and beta-catenin with the ubiquitin-proteasome system. Oncogene 19(16):1992–2001

    CAS  PubMed  Google Scholar 

  153. Strovel ET, Wu D, Sussman DJ (2000) Protein phosphatase 2Calpha dephosphorylates axin and activates LEF-1-dependent transcription. J Biol Chem 275(4):2399–2403

    CAS  PubMed  Google Scholar 

  154. Chen X, Shevtsov SP, Hsich E, Cui L, Haq S, Aronovitz M, Kerkela R, Molkentin JD, Liao R, Salomon RN, Patten R, Force T (2006) The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophy. Mol Cell Biol 26(12):4462–4473

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Zhurinsky J, Shtutman M, Ben-Ze’ev A (2000) Plakoglobin and beta-catenin: protein interactions, regulation and biological roles. J Cell Sci 113(Pt 18):3127–3139

    CAS  PubMed  Google Scholar 

  156. Huelsken J, Vogel R, Brinkmann V, Erdmann B, Birchmeier C, Birchmeier W (2000) Requirement for beta-catenin in anterior-posterior axis formation in mice. J Cell Biol 148(3):567–578

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Miravet S, Piedra J, Miro F, Itarte E, Garcia de Herreros A, Dunach M (2002) The transcriptional factor Tcf-4 contains different binding sites for beta-catenin and plakoglobin. J Biol Chem 277(3):1884–1891

    CAS  PubMed  Google Scholar 

  158. Lombardi R, da Graca Cabreira-Hansen M, Bell A, Fromm RR, Willerson JT, Marian AJ (2011) Nuclear plakoglobin is essential for differentiation of cardiac progenitor cells to adipocytes in arrhythmogenic right ventricular cardiomyopathy. Circ Res 109(12):1342–1353

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Aktary Z, Alaee M, Pasdar M (2017) Beyond cell-cell adhesion: plakoglobin and the regulation of tumorigenesis and metastasis. Oncotarget 8(19):32270–32291

    PubMed  PubMed Central  Google Scholar 

  160. Heallen T, Zhang M, Wang J, Bonilla-Claudio M, Klysik E, Johnson RL, Martin JF (2011) Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332(6028):458–461

    CAS  PubMed  PubMed Central  Google Scholar 

  161. von Gise A, Lin Z, Schlegelmilch K, Honor LB, Pan GM, Buck JN, Ma Q, Ishiwata T, Zhou B, Camargo FD, Pu WT (2012) YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy. Proc Natl Acad Sci U S A 109(7):2394–2399

    Google Scholar 

  162. Hu Y, Pu WT (2014) Hippo activation in arrhythmogenic cardiomyopathy. Circ Res 114(3):402–405

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Hood AR, Ai X, Pogwizd SM (2017) Regulation of cardiac gap junctions by protein phosphatases. J Mol Cell Cardiol 107:52–57

    CAS  PubMed  Google Scholar 

  164. Cooper CD, Lampe PD (2002) Casein kinase 1 regulates connexin-43 gap junction assembly. J Biol Chem 277(47):44962–44968

    CAS  PubMed  Google Scholar 

  165. 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(Pt 16):3435–3442

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Axelsen LN, Stahlhut M, Mohammed S, Larsen BD, Nielsen MS, Holstein-Rathlou NH, Andersen S, Jensen ON, Hennan JK, Kjolbye AL (2006) Identification of ischemia-regulated phosphorylation sites in connexin43: a possible target for the antiarrhythmic peptide analogue rotigaptide (ZP123). J Mol Cell Cardiol 40(6):790–798

    CAS  PubMed  Google Scholar 

  167. Hund TJ, Lerner DL, Yamada KA, Schuessler RB, Saffitz JE (2007) Protein kinase Cepsilon mediates salutary effects on electrical coupling induced by ischemic preconditioning. Heart Rhythm 4(9):1183–1193

    PubMed  PubMed Central  Google Scholar 

  168. Sosinsky GE, Solan JL, Gaietta GM, Ngan L, Lee GJ, Mackey MR, Lampe PD (2007) The C-terminus of connexin43 adopts different conformations in the Golgi and gap junction as detected with structure-specific antibodies. Biochem J 408(3):375–385

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Solan JL, Marquez-Rosado L, Sorgen PL, Thornton PJ, Gafken PR, Lampe PD (2007) Phosphorylation at S365 is a gatekeeper event that changes the structure of Cx43 and prevents down-regulation by PKC. J Cell Biol 179(6):1301–1309

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Jozwiak J, Dhein S (2008) Local effects and mechanisms of antiarrhythmic peptide AAP10 in acute regional myocardial ischemia: electrophysiological and molecular findings. Naunyn Schmiedeberg's Arch Pharmacol 378(5):459–470

    CAS  Google Scholar 

  171. Gilleron J, Fiorini C, Carette D, Avondet C, Falk MM, Segretain D, Pointis G (2008) Molecular reorganization of Cx43, Zo-1 and Src complexes during the endocytosis of gap junction plaques in response to a non-genomic carcinogen. J Cell Sci 121(Pt 24):4069–4078

    CAS  PubMed  Google Scholar 

  172. Kieken F, Mutsaers N, Dolmatova E, Virgil K, Wit AL, Kellezi A, Hirst-Jensen BJ, Duffy HS, Sorgen PL (2009) Structural and molecular mechanisms of gap junction remodeling in epicardial border zone myocytes following myocardial infarction. Circ Res 104(9):1103–1112

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Tamanini A, Nicolis E, Bonizzato A, Bezzerri V, Melotti P, Assael BM, Cabrini G (2006) Interaction of adenovirus type 5 fiber with the coxsackievirus and adenovirus receptor activates inflammatory response in human respiratory cells. J Virol 80(22):11241–11254

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Loustalot F, Kremer EJ, Salinas S (2016) Membrane dynamics and signaling of the Coxsackievirus and adenovirus receptor. Int Rev Cell Mol Biol 322:331–362

    PubMed  Google Scholar 

  175. Marchant D, Sall A, Si X, Abraham T, Wu W, Luo Z, Petersen T, Hegele RG, McManus BM (2009) ERK MAP kinase-activated Arf6 trafficking directs Coxsackievirus type B3 into an unproductive compartment during virus host-cell entry. J Gen Virol 90(Pt 4):854–862

    CAS  PubMed  Google Scholar 

  176. Franke WW, Borrmann CM, Grund C, Pieperhoff S (2006) The area composita of adhering junctions connecting heart muscle cells of vertebrates. I. Molecular definition in intercalated disks of cardiomyocytes by immunoelectron microscopy of desmosomal proteins. Eur J Cell Biol 85(2):69–82

    CAS  PubMed  Google Scholar 

  177. Pieperhoff S, Franke WW (2007) The area composita of adhering junctions connecting heart muscle cells of vertebrates - IV: coalescence and amalgamation of desmosomal and adhaerens junction components - late processes in mammalian heart development. Eur J Cell Biol 86(7):377–391

    CAS  PubMed  Google Scholar 

  178. Pieperhoff S, Barth M, Rickelt S, Franke WW (2010) Desmosomal molecules in and out of adhering junctions: normal and diseased states of epidermal, cardiac and mesenchymally derived cells. Dermatol Res Pract 2010:139167

    PubMed  PubMed Central  Google Scholar 

  179. Wilson AJ, Schoenauer R, Ehler E, Agarkova I, Bennett PM (2014) Cardiomyocyte growth and sarcomerogenesis at the intercalated disc. Cell Mol Life Sci 71(1):165–181

    CAS  PubMed  Google Scholar 

  180. Geisler SB, Green KJ, Isom LL, Meshinchi S, Martens JR, Delmar M, Russell MW (2010) Ordered assembly of the adhesive and electrochemical connections within newly formed intercalated disks in primary cultures of adult rat cardiomyocytes. J Biomed Biotechnol 2010:624719

    PubMed  PubMed Central  Google Scholar 

  181. Agullo-Pascual E, Reid DA, Keegan S, Sidhu M, Fenyo D, Rothenberg E, Delmar M (2013) Super-resolution fluorescence microscopy of the cardiac connexome reveals plakophilin-2 inside the connexin43 plaque. Cardiovasc Res 100(2):231–240

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Oxford EM, Musa H, Maass K, Coombs W, Taffet SM, Delmar M (2007) Connexin43 remodeling caused by inhibition of plakophilin-2 expression in cardiac cells. Circ Res 101(7):703–711

    CAS  PubMed  Google Scholar 

  183. Gehmlich K, Lambiase PD, Asimaki A, Ciaccio EJ, Ehler E, Syrris P, Saffitz JE, McKenna WJ (2011) A novel desmocollin-2 mutation reveals insights into the molecular link between desmosomes and gap junctions. Heart Rhythm 8(5):711–718

    PubMed  PubMed Central  Google Scholar 

  184. 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(6):523–526

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Zemljic-Harpf AE, Godoy JC, Platoshyn O, Asfaw EK, Busija AR, Domenighetti AA, Ross RS (2014) Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin-43-containing gap junctions in cardiac myocytes. J Cell Sci 127(Pt 5):1104–1116

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Agullo-Pascual E, Cerrone M, Delmar M (2014) Arrhythmogenic cardiomyopathy and Brugada syndrome: diseases of the connexome. FEBS Lett 588(8):1322–1330

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Estigoy CB, Ponten F, Odeberg J, Herbert B, Guilhaus M, Charleston M, Ho JWK, Cameron D, Dos Remedios CG (2009) Intercalated discs: multiple proteins perform multiple functions in non-failing and failing human hearts. Biophys Rev 1(1):43

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Soni S, Raaijmakers AJ, Raaijmakers LM, Damen JM, van Stuijvenberg L, Vos MA, Heck AJ, van Veen TA, Scholten A (2016) A proteomics approach to identify new putative cardiac intercalated disk proteins. PLoS One 11(5):e0152231

    PubMed  PubMed Central  Google Scholar 

  189. Davis RP, van den Berg CW, Casini S, Braam SR, Mummery CL (2011) Pluripotent stem cell models of cardiac disease and their implication for drug discovery and development. Trends Mol Med 17(9):475–484

    CAS  PubMed  Google Scholar 

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Funding

This work was supported by a grant from the Canadian Institutes of Health Research (Grant # MOP 125999) and Heart and Stroke Foundation of Canada (G-16-00014152).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada

    Guangze Zhao, Huifang M. Zhang & Decheng Yang

  2. Center for Heart Lung Innovation - St. Paul’s Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada

    Guangze Zhao, Huifang M. Zhang & Decheng Yang

  3. College of Biology, Hunan Universsity, Changsha, China

    Ye Qiu

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  2. Ye Qiu
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  3. Huifang M. Zhang
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  4. Decheng Yang
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Correspondence to Decheng Yang.

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Zhao, G., Qiu, Y., Zhang, H.M. et al. Intercalated discs: cellular adhesion and signaling in heart health and diseases. Heart Fail Rev 24, 115–132 (2019). https://doi.org/10.1007/s10741-018-9743-7

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