Gap Junctions and Connexin Expression in Human Heart Disease

  • Nicholas J. Severs
Part of the Basic Science for the Cardiologist book series (BASC, volume 12)


Sequential contraction of the cardiac chambers depends on orderly spread of the wave of electrical excitation from one cardiomyocyte to the next, throughout the heart. As discussed in earlier chapters of this volume, the pathways enabling this cell-to-cell current flow are formed by the gap junctions that link individual cardiomyocytes into a functional syncytium. Gap junctions are essentially clusters of transmembrane channels that span the paired plasma membranes of neighboring cells, linking their cytoplasmic compartments together to form pathways for direct cell-to-cell communication. The component proteins of the gap-junctional channel, connexins, are assembled into hexamers which form hemi-channels termed connexons, the complete channel being formed by the docking of a pair of connexons across the adjacent plasma membranes. Twenty different connexin genes have now been identified in the human (Willecke et al., 2001), and most tissues, including those of the cardiovascular system, express two or more connexin isoforms. Three principal isoforms — connexin43, connexin40 and connexin45 — are expressed in cardiomyocytes (reviews, Beyer et al., 1997; Severs, 1999; Severs et al., 2001), and further isoforms such as connexin46 (Paul et al., 1991) and connexin57 (Manthey et al., 1999) may also be present in trace amounts. Gapjunctional channels composed of different connexins exhibit distinctive biophysical properties in vitro (review, Bruzzone et aI., 1996), and studies on transgenic mice demonstrate that the precise functional properties of gap junctions in vivo may depend in part on the specific connexins from which they are constructed, though there is also considerable capacity for functional compensation of one connexin isoform by another (Kirchhoff et al., 2000; KrUger et al., 2000; Plum et al., 2000; Tamaddon et al., 2000; van ijen et al., 2001). Different subsets of cardiomyocyte express different combinations and relative quantities of connexins 43, 40 and 45, potentially providing for regional differentiation of electrophysiological properties. The concept has thus developed that gap junction organization and spatially defined patterns of connexin expression may preside over the precisely or chestrated patterns of current flow that govern the normal heart rhythm.


Intercalate Disk Connexin Expression Human Heart Disease Rabbit Sinoatrial Node Distinctive Biophysical Property 
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  1. Bastide, B., Neyses, L., Ganten, D., Paul, M., Willecke, K., and Traub, O. 1993. Gap junction protein connexin40 is preferentially expressed in vascular endothelium and conductive bundles of rat myocardium and is increased under hypertensive conditions. Circ Res 73, 1138–49.PubMedCrossRefGoogle Scholar
  2. Beyer, E., Seul, K. H., and Larson, D. M. 1997. Cardiovascular gap junction proteins: molecular characterization and biochemical regulation. In Heart Cell Communication in Health and Disease. De Mello, W. C., Janse, M. J., and Norwell, M. A., editors. (Kluwer Academic Publications New York), pp. 45–51.Google Scholar
  3. Beyer, E.C., Kistler, J., Paul, D. L., and Goodenough, D. A. 1989. Antisera directed against connexin43 peptides react with a 43-kd protein localized to gap junctions in myocardium and other tissues. J Cell Biol 108, 595–605.PubMedCrossRefGoogle Scholar
  4. Bruzzone, R., White, T. W., and Paul, D. L. 1996. Connections with connexins: The molecular basis of direct intercellular signaling. Eur J Biochem 238, 1–27.PubMedCrossRefGoogle Scholar
  5. Bukauskas, F.F., Elfgang, C., Willecke, K., and Weingart, R. 1995. Biophysical properties of gap junction channels formed by mouse connexin40 in induced pairs of transfected human HeLa cells. Biophys J 68, 2289–98.PubMedCrossRefGoogle Scholar
  6. Cohn, E.S., and Kelley, P. M. 1999. Clinical phenotype and mutations in connexin 26 (DFNBI/GJB2), the most common cause of childhood hearing loss. Am J Med Genet 89, 130–6.PubMedCrossRefGoogle Scholar
  7. Coppen, S.R., Dupont, E., Rothery, S., and Severs, N. J. 1998. Connexin45 expression is preferentially associated with the ventricular conduction system in mouse and rat heart. Circ Res 82, 232–43.PubMedCrossRefGoogle Scholar
  8. Coppen, S.R., Gourdie, R. G., and Severs, N. J. 2001. Connexin45 is the first connexin to be expressed in the central conduction system of the mouse heart. Exp Clin Cardiol 6, 17–23.PubMedGoogle Scholar
  9. Coppen, S.R., Kodama, I., Boyett, M. R., Dobrzynski, H., Takagishi, Y., Honjo, H., Yeh, H.-I., and Severs, N. J. 1999a. Connexin45, a major connexin of the rabbit sinoatrial node, is co-expressed with connexin43 in a restricted zone at the nodalcrista terminalis border. J Histochem Cytochem 47, 907–18.PubMedCrossRefGoogle Scholar
  10. Coppen, S.R., Severs, N. J., and Gourdie, R. G. 1999b. Connexin45 (a6) expression delineates an extended conduction system in the embryonic and mature rodent heart. Dev Genet 24, 82–90.PubMedCrossRefGoogle Scholar
  11. Dasgupta, C., Escobar-Poni, B., Shah, M., Duncan, J., and Fletcher, W. H. 1999. Misregulation of connexin43 gap junction channels and congenital heart defects. In Gap Junction-Mediated Intercellular Signalling in Health and Disease. Cardew, G., editor. (John Wiley & Sons Ltd. New York), pp. 212–21.Google Scholar
  12. Dupont, E., Ko, Y. S., Rothery, S., Coppen, S. R., Baghai, M., Haw, M., and Severs, N. J. 2001. The gap junctional protein, connexin40, is elevated in patients susceptible to post-operative atrial fibrillation. Circulation 103, 842–9.PubMedCrossRefGoogle Scholar
  13. Dupont, E., Matsushita, T., Kaba, R., Vozzi, C., Coppen, S. R., Khan, N., Kaprielian, R., Yacoub, M. H., and Severs, N. J. 2001. Altered connexin expression in human congestive heart failure. J Mol Cell Cardiol 33, 359–71.PubMedCrossRefGoogle Scholar
  14. Emdad, L., Uzzaman, M., Takagishi, Y., Honjo, H., Uchida, T., Severs, N. J., Kodama, I., and Murata, Y. 2001. Gap junction remodelling in hypertrophied left ventricles of aortic-banded rats: prevention by angiotensin Il typel receptor blockade. J Mol Cell Cardiol 33, 219–31.PubMedCrossRefGoogle Scholar
  15. Gourdie, R.G., Green, C. R., and Severs, N. J. 1991. Gap junction distribution in adult mammalian myocardium revealed by an antipeptide antibody and laser scanning confocal microscopy. J Cell Sci 99, 41–55.PubMedGoogle Scholar
  16. Gourdie, R.G., Severs, N. J., Green, C. R., Rothery, S., Germroth, P., and Thompson, R. P. 1993. The spatial distribution and relative abundance of gap junctional connexin40 and connexin43 correlate to functional properties of the cardiac atrioventricular conduction system. J Cell Sci 105, 985–91.PubMedGoogle Scholar
  17. Green, C.R., and Severs, N. J. 1993. Distribution and role of gap junctions in normal myocardium and human ischaemic heart disease. Histochemistry 99, 105–20.PubMedCrossRefGoogle Scholar
  18. Gros, D., Jarry-Guichard, T., ten Velde, L, De Mazière, A. M. G. L., Van Kempen, M. J. A., Davoust, J., Briand, J. P., Moorman, A. F. M., and Jongsma, H. J. 1994. Restricted distribution of connexin40, a gap junctional protein, in mammalian heart. Circ Res 74, 839–51.PubMedCrossRefGoogle Scholar
  19. Gutstein, D.E., Morley, G. E., Tamaddon, H., Vaidya, D., Schneider, M. D., Chen, J., Chien, K. R., Stuhlmann, H., and Fishman, G. I. 2001. Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivitation of connexin43. Circ Res 88, 333–9.PubMedCrossRefGoogle Scholar
  20. Gutstein, D.E., Morley, G. E., Vaidya, D., Liu, F., Chen, F. L., Stuhlmann, H., and Fishman, G. I. 2001. Heterogeneous expression of gap junction channels in the heart leads to conduction defects and ventricular dysfunction. Circulation 104, 1194–9.PubMedCrossRefGoogle Scholar
  21. Hagendorff, A., Schumacher, B., Kirchhoff S., Luderitz, B., and Willecke, K. 1999. Conduction disturbances and increased atrial vulnerability in connexin40defficient mice analyzed by transesophageal stimilation. Circulation 99, 1508–15.PubMedCrossRefGoogle Scholar
  22. Honjo, H., Boyett, M. R., Coppen, S. R., Takagishi, Y., Severs, N. J., and Kodama, I. 2002. Heterogeneous expression of connexins in rabbit sinoatrial node cells: correlation between connexin isoform and cell size. Cardiovasc Res in press..Google Scholar
  23. Jongsma, H.J., and Wilders, R. 2000. Gap junctions in cardiovascular disease. Cire Res 86, 1193–7.CrossRefGoogle Scholar
  24. Kaprielian, R.R., Gunning, M., Dupont, E., Sheppard, M. N., Rothery, S. M., Underwood, R., Pennell, D. J., Fox, K., Pepper, J., Poole-Wilson, P. A., and Severs, N. J. 1998. Down-regulation of immunodetectable connexin43 and decreased gap junction size in the pathogenesis of chronic hibernation in the human left ventricle. Circulation 97, 651–60.PubMedCrossRefGoogle Scholar
  25. Kirchhoff, S., Kim, J. S., Hagendorff, A., Thonnissen, E., Kruger, O., Lamers, W. H., and Willecke, K. 2000. Abnormal cardiac conduction and morphogenesis in connexin40 and connexin43 double-deficient mice. Cire Res 87, 399–405.CrossRefGoogle Scholar
  26. Kirchhoff, S., Nelles, E., Hagendorff, A., Krüger, O., Traub, O., and Willecke, K. 1998. Reduced cardiac conduction velocity and predisposition to arrhythmias in connexin40-deficient mice. Curr Biol 8, 299–302.PubMedCrossRefGoogle Scholar
  27. Krüger, O., Plum, A., Kim, J.-S., Winterhager, E., Maxeiner, S., Hallas, G., Kirchhoff, Traub, O., Lamers, W. H., and Willecke, K. 2000. Defective vascular development in connexin 45-deficient mice. Development 127, 4179–93.Google Scholar
  28. Lerner, D.L., Yamada, K. A., Schuessler, R. B., and Saffitz, J. E. 2000 Accelerated onset and increased incidence of ventricular arrhythmias induced by ischaemia in Cx43-deficient mice. Circulation 101, 547–52.PubMedCrossRefGoogle Scholar
  29. Mackay, D., lonides, A., Kibar, Z., Rouleau, G., Berry, V., Moore, A., Shiels, A., and Bhattacharya, S. 1999. Connexin46 mutations in autosomal dominant congenital cataract. Am J Hum Genet 64, 1357–64.PubMedCrossRefGoogle Scholar
  30. Manthey, D., Bukauskas, F., Lee, C. G., Kozak, C. A., and Willecke, K. 1999. Molecular cloning and functional expression of the mouse gap junction gene connexin-57 in human HeLa cells. J Biol Chem 274, 14716–23.PubMedCrossRefGoogle Scholar
  31. Matsushita, T., Oyamada, M., Fujimoto, K., Yasuda, Y., Masuda, S., Wada, Y., Oka T., and Takamatsu, T. 1999. Remodelling of cell-cell and cell-extracellular matrix interactions at the border zone of rat myocardial infarcts. Circ Res 85, 1046–55.PubMedCrossRefGoogle Scholar
  32. Moreno, A.L., Laing, J. G., Beyer, E. C., and Spray, D. C. 1995. Properties of gap junction channels formed of connexin 45 endogenously expressed in human hepatoma (SKHep1) cells. Am J Physiol 268, C356–C365.PubMedGoogle Scholar
  33. Paul, D.L., Ebihara, L., Takemoto, L. J., Swenson, K. I., and Goodenough, D. A. 1991 Connexin46, a novel lens gap junction protein, induces voltage-gated currents in nonjunctional plasma membrane ofXenopusoocytes. J Cell Biol 115, 1077–89.PubMedCrossRefGoogle Scholar
  34. Plum, A., Hallas, G., Magin, T., Dombrowski, F., Hagendorff, A., Schumacher, B., Wolpert, C., Kim, J.-S., Lamers, W. H., Evert, M., Meda, P., Traub, O., and Willecke, K. 2000. Unique and shared functions of different connexins in mice. Curr Biol 10, 1083–91.PubMedCrossRefGoogle Scholar
  35. Rohr, S., Kucera, J. P., Fast, V. G., and Kleber, A. G. 1997. Paradoxical improvement of impulse conduction in cardiac tissue by partial cellular uncoupling. Science 275, 841–4.PubMedCrossRefGoogle Scholar
  36. Rudy, Y., and Shaw, R. M. 1997. Cardiac excitation: an interactive process of ion channels and gap junctions. Adv Exp Med Biol 430, 269–79.PubMedCrossRefGoogle Scholar
  37. Saffitz, J. E., Beyer, E. C., Darrow, B. J., Guerrero, P. A., Beardslee, M. A., and Dodge, S. M. 1997. Gap junction structure, conduction, and arrhhythmogenesis: direction for future research. In Discontinuous Conduction in the Heart. Spooner, P. M., Joyner, R. W., and Jalife, J., editors. (Futura Publishing Company New York), pp. 89–105.Google Scholar
  38. Scherer, S.S., Bone, L. J., Deschenes, S. M., Abel, A., Balice-Gordon, R. J., and Fischbeck, K. H. 1999. The role of the gap junction protein connexin32 in the pathogenesis of X-linked Charcot-Marie-Tooth disease. Novartis Found Symp 219, 175–85.PubMedGoogle Scholar
  39. Sepp, R., Severs, N.J., and Gourdie, R.G. 1996 Altered patterns of intercellular junction distribution in hypertrophic cardiomyopathy. Heart 76, 412–417.PubMedCrossRefGoogle Scholar
  40. Severs, N. J. 1989. Constituent cells of the heart and isolated cell models in cardiovascular research. In Isolated Adult Cardiomyocytes. volume 1. Piper, H. M., and Isenberg, G., editors. (CRC Press Inc. Boca Raton), pp. 3–41.Google Scholar
  41. Severs, N. J. 1998. Gap junctions and coronary heart disease. In Heart Cell Communication in Health and Disease. De Mello, W. C., and Janse, M. J., editors. (Kluwer Boston), pp. 175–94.Google Scholar
  42. Severs, N. J. 1999. Cardiovascular disease. In Gap Junction-Mediated Intercellular Signalling in Health and Disease. Cardew, G., editor. (John Wiley & Sons Ltd. New York), pp. 188–206.Google Scholar
  43. Severs, N.J. 2000. The cardiac muscle cell. BioEssays 22, 188–99.PubMedCrossRefGoogle Scholar
  44. Severs, N. J., Dupont, E., Kaprielian, R. R., Yeh, H.-I., and Rothery, S. 1996. Gap junctions and connexins in the cardiovascular system. In Annual of Cardiac Surgery 1996: 9`hedition. Yacoub, M. H., Carpentier, A., Pepper, J., and Fabiani, J.-N., editors. (Current Science London), pp. 31–44.Google Scholar
  45. Severs, N.J., Gourdie, R. G., Harfst, E., Peters, N. S., and Green, C. R. 1993. Review. Intercellular junctions and the application of microscopical techniques: the cardiac gap junction as a case model. J Microsc 169, 299–328.PubMedCrossRefGoogle Scholar
  46. Severs, N.J., Rothery, S., Dupont, E., Coppen, S. R., Yeh, H.-I., Ko, Y.-S., Matsushita, T., Kaba, R., and Halliday, D. 2001 Immunocytochemical analysis of connexin expression in the healthy and diseased cardiovascular system. Microsc Res Tech 52, 301–22.PubMedCrossRefGoogle Scholar
  47. Shaw, R.M., and Rudy, Y. 1997 Ionic mechanisms of propagation in cardiac tissue Roles of the sodium and L-type calcium currents during reduced excitability and decreased gap junction coupling. Cire Res 81, 727–41.CrossRefGoogle Scholar
  48. Simon, A.M., Goodenough, D. A., and Paul, D. L. 1998. Mice lacking connexin40 have cardiac conduction abnormalities characteristic of atrioventricular block and bundle branch block. Curr Biol 8, 295–8.PubMedCrossRefGoogle Scholar
  49. Smith, J.H., Green, C. R., Peters, N. S., Rothery, S., and Severs, N. J. 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, 801–21.PubMedGoogle Scholar
  50. Spach MS, Heidlage JF, Dolber PC, Barr RC. 2000. Electrophysiological effects of remodelling cardiac gap junctions and cell size. Circ Res 86: 302–311.PubMedCrossRefGoogle Scholar
  51. Tamaddon, H.S., Vaidya, D., Simon, A. M., Paul, D. L., Jalife, J., and Morley, G. E. 2000 High-resolution optical mapping of the right bundle branch in connexin40 knockout mice reveals slow conduction in the specialized conduction system. Cire Res 87, 929–36.CrossRefGoogle Scholar
  52. Uzzaman, M., Honjo, H., Takagishi, Y, Emdad, L., Magee, A. I., Severs, N. J., and Kodama, I. 2000. Remodeling of gap junctional coupling in hypertrophied right ventricles of rats with monocrotaline-induced pulmonary hypertension. Cire Res 86, 871–8.CrossRefGoogle Scholar
  53. van Rijen, H.V.M., Van Veen, T. A. B., Van Kempen, M. J. A., Wilms-Schopman, F. J. G., Poste, M., Krueger, O., Willecke, K., Opthof, T., Jongsma, H. J., and de Bakker, J. M. T. 2001 Impaired conduction in the bundle branches of mouse hearts lacking the gap junction protein connexin40. Circulation 103, 1591–8.PubMedCrossRefGoogle Scholar
  54. Viswanathan, P.C., Shaw, R. M., and Rudy, Y. 1999. Effects of IKr and IKs heterogeneity on action potential duration and its rate dependence: a simulation study. Circulation 99, 2466–74.PubMedCrossRefGoogle Scholar
  55. Vozzi, C., Dupont, E., Coppen, S. R., Yeh, H.-I., and Severs, N. J. 1999. Chamber-related differences in connexin expression in the human heart. J Mol Cell Cardiol 31, 991–1003.PubMedCrossRefGoogle Scholar
  56. Willecke K, Eiberger J, Degen J, Eckardt D, Romualdi A, Gueldenagel M, Deutsch U, Soehl G. 2001. Structural and functional diversity of connexin genes in the mouse and human genome. Biol Chem in press.Google Scholar
  57. Yeh, H.-I., Dupont, E., Coppen, S., Rothery, S., and Severs, N. J. 1997a. Gap junction localization and connexin expression in cytochemically identified endothelial cells from arterial tissue. J Histochem Cytochem 45, 539–50.CrossRefGoogle Scholar
  58. Yeh, H.-I., Dupont, E., Rothery, S., Coppen, S. R., and Severs, N. J. (1998). Individual gap junction plaques contain multiple connexins in arterial endothelium. Circ Res 83, 1248–63.PubMedCrossRefGoogle Scholar
  59. Yeh, H.-I., Lai, Y.-J., Chang, H.-M., Ko, Y.-S., Severs, N. J., and Tsai, C.-H. (2000). Multiple connexin expression in regenerating arterial endothelial gap junctions. Arterioscler Thromb Vasc Biol 20, 1753–62.PubMedCrossRefGoogle Scholar
  60. Yeh, H.-I., Lupu, F., Dupont, E., and Severs, N. J. (1997b). Upregulation of connexin43 gap junctions between smooth muscle cells after balloon catheter injury in the rat carotid artery. Arterioscler Thromb Vase Biol 17, 3174–84.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Nicholas J. Severs
    • 1
  1. 1.National Heart and Lung InstituteFaculty of Medicine, Imperial College, Royal BromptonLondonUK

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