Gap Junctions formed by Connexin 43: from Normal Function to Physiological Impact in its Change in the Cardiovascular System
DOI:
https://doi.org/10.47941/ijbs.2367Keywords:
Gap junction, Connexin 43, Cardiovascular SystemAbstract
Purpose: This study highlights the role of gap junctions that allow communication between adjacent cells and in the cardiovascular system, with the most abundant isoform being connexin 43, providing the basis for intercellular communication, allowing the transfer of small molecules and the propagation of calcium waves in cardiomyocytes. This review aims to provide the main information on the role of connexin 43 in the cardiovascular system and to address the pathologies associated with its alteration.
Methodology: a search was carried out in the databases of the CAPES journal portal, Scielo, Scopus, Science Direct and PubMed using keywords and selecting the articles with the inclusion and exclusion criteria to structure a work aimed at students and researchers in the areas of cell biology, biophysics and physiology.
Findings: This study investigated the functional and structural anomalies of Cx43 in cardiac pathologies, highlighting that the lateralization of this protein is a recurrent event in several cardiovascular diseases, often associated with dysfunctions in the rhythms and electrical conduction of the heart. Furthermore, the role of Cx43 in mitochondria was analyzed, a recently recognized aspect that has aroused increasing interest. The results indicate that alterations in Cx43 may represent a promising therapeutic target, offering new perspectives for the development of clinical disciplines in cardiac diseases.
Unique contribution to theory, practice and policy: A consolidated analysis of the demonstrated evidence suggests that gap junctions, composed of different isoforms of connections, play an essential role in the transmission of the cardiac electrical impulse. From these findings, it can be inferred that both genetic diseases and acquired pathologies are associated with modifications in the levels and subcellular distribution of connexin. Changes in the expression and positioning of these proteins can therefore trigger the worsening of pathological conditions, compromising cardiac function and enhancing the development of electrical conduction dysfunctions. In this context, connections emerge as promising targets for the development of therapeutic strategies, offering new perspectives for the treatment of a wide range of cardiac diseases.
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References
AASEN, Trond et al. Connexins in cancer: bridging the gap to the clinic. Oncogene, v. 38, n. 23, p. 4429-4451, 2019.
AASEN, Trond et al. Connexins: synthesis, post-translational modifications, and trafficking in health and disease. International journal of molecular sciences, v. 19, n. 5, p. 1296, 2018.
ARELLANO, R. O.; RIVERA, A.; RAMON, F. Protein phosphorylation and hydrogen ions modulate calcium-induced closure of gap junction channels. Biophysical journal, v. 57, n. 2, p. 363-367, 1990.
ARELLANO, R. O.; RIVERA, A.; RAMON, F. Protein phosphorylation and hydrogen ions modulate calcium-induced closure of gap junction channels. Biophysical journal, v. 57, n. 2, p. 363-367, 1990.
BASHEER, Wassim; SHAW, Robin. The “tail” of Connexin43: An unexpected journey from alternative translation to trafficking. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, v. 1863, n. 7, p. 1848-1856, 2016.
BEAUCHAMP, Philippe et al. Relative contributions of connexins 40 and 43 to atrial impulse propagation in synthetic strands of neonatal and fetal murine cardiomyocytes. Circulation research, v. 99, n. 11, p. 1216-1224, 2006.
BENNETT, Michael VL et al. Gap junctions: new tools, new answers, new questions. Neuron, v. 6, n. 3, p. 305-320, 1991.
BEYER, E. C. et al. Cardiac intercellular communication: consequences of connexin distribution and diversity. Brazilian Journal of Medical and Biological Research= Revista Brasileira de Pesquisas Medicas e Biologicas, v. 28, n. 4, p. 415-425, 1995.
BOENGLER, Kerstin; SCHULZ, Rainer. Connexin 43 and mitochondria in cardiovascular health and disease. Mitochondrial Dynamics in Cardiovascular Medicine, p. 227-246, 2017.
BRITZ-CUNNINGHAM, Scott H. et al. Mutations of the Connexin43 gap-junction gene in patients with heart malformations and defects of laterality. New England Journal of Medicine, v. 332, n. 20, p. 1323-1330, 1995.
BRUZZONE, Roberto; RESSOT, Catherine. Connexins, gap junctions and cell‐cell signalling in the nervous system. European Journal of Neuroscience, v. 9, n. 1, p. 1-6, 1997.
BRUZZONE, Roberto; WHITE, Thomas W.; GOODENOUGH, Daniel A. The cellular internet: on‐line with connexins. Bioessays, v. 18, n. 9, p. 709-718, 1996.
BRUZZONE, Santina et al. Connexin 43 hemi channels mediate Ca2+-regulated transmembrane NAD+ fluxes in intact cells. The FASEB Journal, v. 15, n. 1, p. 10-12, 2001.
CAO, Dongrong et al. Mechanisms for the coordination of intercellular calcium signaling in insulin-secreting cells. Journal of Cell Science, v. 110, n. 4, p. 497-504, 1997.
CHANSON, Marc et al. Gap junctional communication in tissue inflammation and repair. Biochimica et Biophysica Acta (BBA)-Biomembranes, v. 1711, n. 2, p. 197-207, 2005.
CHERIAN, Priscilla P. et al. Mechanical strain opens connexin 43 hemichannels in osteocytes: a novel mechanism for the release of prostaglandin. Molecular biology of the cell, v. 16, n. 7, p. 3100-3106, 2005.
CONTRERAS, Jorge E. et al. Role of connexin-based gap junction channels and hemichannels in ischemia-induced cell death in nervous tissue. Brain Research Reviews, v. 47, n. 1-3, p. 290-303, 2004.
COSCARELLA, Isabella Leite et al. Arrhythmogenic cardiomyopathy: exercise pitfalls, role of connexin-43, and moving beyond antiarrhythmics. International Journal of Molecular Sciences, v. 23, n. 15, p. 8753, 2022.
CRUCIANI, Véronique; MIKALSEN, Svein‐Ole. Connexins, gap junctional intercellular communication and kinases. Biology of the Cell, v. 94, n. 7‐8, p. 433-443, 2002.
DALE, Nicholas. Dynamic ATP signalling and neural development. The Journal of physiology, v. 586, n. 10, p. 2429-2436, 2008.
DAVIS, Lloyd M. et al. Distinct gap junction protein phenotypes in cardiac tissues with disparate conduction properties. Journal of the American College of Cardiology, v. 24, n. 4, p. 1124-1132, 1994.
DE CARVALHO, Gabriella Oliveira Alves Moreira et al. Junction communication in the immune system: modulation of the GAP junctions by infection with Toxoplasma gondii. Brazilian Journal of Development, v. 7, n. 1, p. 4165-4182, 2021.
DE MAIO, Antonio; VEGA, Virginia L.; CONTRERAS, Jorge E. Gap junctions, homeostasis, and injury. Journal of cellular physiology, v. 191, n. 3, p. 269-282, 2002.
DERMIETZEL, Rolf; SPRAY, David C. Gap junctions in the brain: where, what type, how many and why?. Trends in neurosciences, v. 16, n. 5, p. 186-192, 1993.
DESPLANTEZ, Thomas et al. Gap junction channels and cardiac impulse propagation. Journal of Membrane Biology, v. 218, p. 13-28, 2007.
DHEIN, Stefan. Gap junction channels in the cardiovascular system: pharmacological and physiological modulation. Trends in pharmacological sciences, v. 19, n. 6, p. 229-241, 1998.
DOBLE, Bradley W.; KARDAMI, Elissavet. Basic fibroblast growth factor stimulates connexin-43 expression and intercellular communication of cardiac fibroblasts. Molecular and cellular biochemistry, v. 143, p. 81-87, 1995.
DUTHE, Fabien et al. Endogenous protein phosphatase 1 runs down gap junctional communication of rat ventricular myocytes. American Journal of Physiology-Cell Physiology, v. 281, n. 5, p. C1648-C1656, 2001.
EVANS, W. Howard; MARTIN, Patricia EM. Gap junctions: structure and function. Molecular membrane biology, v. 19, n. 2, p. 121-136, 2002.
FIGUEROA, Xavier F.; DULING, Brian R. Gap junctions in the control of vascular function. Antioxidants & redox signaling, v. 11, n. 2, p. 251-266, 2009.
FLAGG-NEWTON, Jean; SIMPSON, Ian; LOEWENSTEIN, Werner R. Permeability of the cell-to-cell membrane channels in mammalian cell juncton. Science, v. 205, n. 4404, p. 404-407, 1979.
FORTES, Fabio SA et al. Modulation of intercellular communication in macrophages: possible interactions between GAP junctions and P2 receptors. Journal of Cell Science, v. 117, n. 20, p. 4717-4726, 2004.
FROMAGET, Catherine; EL AOUMARI, Abdelhakim; GROS, Daniel. Distribution pattern of connexin 43, a gap junctional protein, during the differentiation of mouse heart myocytes. Differentiation, v. 51, n. 1, p. 9-20, 1992.
GIEPMANS, Ben NG. Gap junctions and connexin-interacting proteins. Cardiovascular research, v. 62, n. 2, p. 233-245, 2004.
GOUBAEVA, Farida et al. Cardiac mitochondrial connexin 43 regulates apoptosis. Biochemical and biophysical research communications, v. 352, n. 1, p. 97-103, 2007.
GREEN, Colin R.; SEVERS, Nicholas J. Distribution and role of gap junctions in normal myocardium and human ischaemic heart disease. Histochemistry, v. 99, n. 2, p. 105-120, 1993.
GUTSTEIN, David E. et al. Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circulation research, v. 88, n. 3, p. 333-339, 2001.
HANSSON, Elisabeth; SKIÖLDEBRAND, Eva. Coupled cell networks are target cells of inflammation, which can spread between different body organs and develop into systemic chronic inflammation. Journal of Inflammation, v. 12, n. 1, p. 44, 2015.
HERVÉ, Jean-Claude; BOURMEYSTER, Nicolas; SARROUILHE, Denis. Diversity in protein–protein interactions of connexins: emerging roles. Biochimica et Biophysica Acta (BBA)-Biomembranes, v. 1662, n. 1-2, p. 22-41, 2004.
HERVÉ, Jean-Claude; DERANGEON, Mickaël. Gap-junction-mediated cell-to-cell communication. Cell and tissue research, v. 352, p. 21-31, 2013.
HESKETH, Geoffrey G.; VAN EYK, Jennifer E.; TOMASELLI, Gordon F. Mechanisms of gap junction traffic in health and disease. Journal of cardiovascular pharmacology, v. 54, n. 4, p. 263-272, 2009.
HIMELMAN, Eric et al. Prevention of connexin-43 remodeling protects against Duchenne muscular dystrophy cardiomyopathy. The Journal of clinical investigation, v. 130, n. 4, p. 1713-1727, 2020.
KADLE, R.; ZHANG, J. T.; NICHOLSON, B. J. Tissue-specific distribution of differentially phosphorylated forms of Cx43. Molecular and Cellular Biology, 1991.
KANG, Man et al. Cx43 phosphorylation on S279/282 and intercellular communication are regulated by IP 3/IP 3 receptor signaling. Cell Communication and Signaling, v. 12, p. 1-12, 2014.
KAR, Rekha et al. Biological role of connexin intercellular channels and hemichannels. Archives of biochemistry and biophysics, v. 524, n. 1, p. 2-15, 2012.
KNEZL, Vladimir et al. Distinct lethal arrhythmias susceptibility is associated with sex-related difference in myocardial connexin-43 expression. Neuroendocrinology Letters, v. 29, n. 5, p. 798, 2008.
KOHL, Peter; GOURDIE, Robert G. Fibroblast–myocyte electrotonic coupling: does it occur in native cardiac tissue?. Journal of molecular and cellular cardiology, v. 70, p. 37-46, 2014.
KONDO, Richard P. et al. Metabolic inhibition activates a non-selective current through connexin hemichannels in isolated ventricular myocytes. Journal of molecular and cellular cardiology, v. 32, n. 10, p. 1859-1872, 2000.
KOSTIN, Sawa. Zonula occludens‐1 and connexin 43 expression in the failing human heart. Journal of cellular and molecular medicine, v. 11, n. 4, p. 892-895, 2007.
KUMAR, N. M. & GILULA, N. B.. The gap junction communication channel. Cell Press 84, 381-388. 1996
LAMPE, Paul D. et al. Analysis of phosphorylation of connexin43 at S325/328/330 in normoxic and ischemic heart. Journal of cell science, v. 119, n. Pt 16, p. 3435, 2006.
LAMPE, Paul D.; LAU, Alan F. The effects of connexin phosphorylation on gap junctional communication. The international journal of biochemistry & cell biology, v. 36, n. 7, p. 1171-1186, 2004.
LAU, Alan F.; HATCH-PIGOTT, Virginia; CROW, David S. Evidence that heart connexin43 is a phosphoprotein. Journal of molecular and cellular cardiology, v. 23, n. 6, p. 659-663, 1991.
LEITHE, Edward; MESNIL, Marc; AASEN, Trond. The connexin 43 C-terminus: A tail of many tales. Biochimica et Biophysica Acta (BBA)-Biomembranes, v. 1860, n. 1, p. 48-64, 2018.
LILLO, Mauricio A. et al. Remodeled connexin 43 hemichannels alter cardiac excitability and promote arrhythmias. Journal of General Physiology, v. 155, n. 7, p. e202213150, 2023.
LILLY, Evelyn et al. Connexin channels in congenital skin disorders. In: Seminars in cell & developmental biology. Academic Press, 2016. p. 4-12.
LIN, Xianming; XU, Qin; VEENSTRA, Richard D. Functional formation of heterotypic gap junction channels by connexins-40 and-43. Channels, v. 8, n. 5, p. 433-443, 2014.
LUKE, R. A. et al. Quantitative analysis of intercellular connections by immunohistochemistry of the cardiac gap junction protein connexin43. Circulation research, v. 65, n. 5, p. 1450-1457, 1989.
MAKOWSKI, Lee et al. Gap junction structures: Analysis of the x-ray diffraction data. The Journal of cell biology, v. 74, n. 2, p. 629-645, 1977.
MEENS, Merlijn J.; KWAK, Brenda R.; DUFFY, Heather S. Role of connexins and pannexins in cardiovascular physiology. Cellular and molecular life sciences, v. 72, p. 2779-2792, 2015.
MEŞE, Gülistan; RICHARD, Gabriele; WHITE, Thomas W. Gap junctions: basic structure and function. Journal of Investigative Dermatology, v. 127, n. 11, p. 2516-2524, 2007.
MICHELA, Pecoraro et al. Role of connexin 43 in cardiovascular diseases. European journal of pharmacology, v. 768, p. 71-76, 2015.
MOREL, Sandrine; R KWAK, Brenda. Roles of connexins in atherosclerosis and ischemia-reperfusion injury. Current pharmaceutical biotechnology, v. 13, n. 1, p. 17-26, 2012.
MORENO, Alonso P. Biophysical properties of homomeric and heteromultimeric channels formed by cardiac connexins. Cardiovascular research, v. 62, n. 2, p. 276-286, 2004.
NEIJSSEN, Joost et al. Cross-presentation by intercellular peptide transfer through gap junctions. Nature, v. 434, n. 7029, p. 83, 2005.
NEIJSSEN, Joost; PANG, Baoxu; NEEFJES, Jacques. Gap junction-mediated intercellular communication in the immune system. Progress in biophysics and molecular biology, v. 94, n. 1-2, p. 207-218, 2007.
NIELSEN, Morten S. et al. The intercalated disc: a unique organelle for electromechanical synchrony in cardiomyocytes. Physiological Reviews, v. 103, n. 3, p. 2271-2319, 2023.
NIELSEN, Morten Schak et al. Gap junctions. Comprehensive physiology, v. 2, n. 3, 2012.
PERACCHIA, Camillo. Chemical gating of gap junction channels: roles of calcium, pH and calmodulin. Biochimica et Biophysica Acta (BBA)-Biomembranes, v. 1662, n. 1-2, p. 61-80, 2004.
REAUME, Andrew G. et al. Cardiac malformation in neonatal mice lacking connexin43. Science, v. 267, n. 5205, p. 1831-1834, 1995.
RODRIGUEZ-SINOVAS, Antonio et al. Translocation of connexin 43 to the inner mitochondrial membrane of cardiomyocytes through the heat shock protein 90–dependent TOM pathway and its importance for cardioprotection. Circulation research, v. 99, n. 1, p. 93-101, 2006.
ROG-ZIELINSKA, Eva A. et al. The living scar–cardiac fibroblasts and the injured heart. Trends in molecular medicine, v. 22, n. 2, p. 99-114, 2016.
ROOK, M. B. et al. Gap junction formation and functional interaction between neonatal rat cardiocytes in culture: a correlative physiological and ultrastructural study. The Journal of membrane biology, v. 118, p. 179-192, 1990.
ROUACH, N. et al. Gap junctions and connexin expression in the normal and pathological central nervous system. Biology of the Cell, v. 94, n. 7‐8, p. 457-475, 2002.
SÁEZ, Juan C. et al. Plasma membrane channels formed by connexins: their regulation and functions. Physiological reviews, v. 83, n. 4, p. 1359-1400, 2003
SAFFITZ, Jeffrey E.; SCHUESSLER, Richard B. Connexin-40, bundle-branch block, and propagation at the Purkinje-myocyte junction. Circulation research, v. 87, n. 10, p. 835-836, 2000.
SCHULTZ, Jacob G. et al. Evaluation of cardiac electrophysiological properties in an experimental model of right ventricular hypertrophy and failure. Cardiology in the young, v. 26, n. 3, p. 451-458, 2016.
SEGRETAIN, Dominique; FALK, Matthias M. Regulation of connexin biosynthesis, assembly, gap junction formation, and removal. Biochimica et Biophysica Acta (BBA)-Biomembranes, v. 1662, n. 1-2, p. 3-21, 2004.
SEPP, Robert; SEVERS, Nicholas J.; GOURDIE, Robert G. Altered patterns of cardiac intercellular junction distribution in hypertrophic cardiomyopathy. Heart, v. 76, n. 5, p. 412-417, 1996.SCHWANKE, Uwe et al. No ischemic preconditioning in heterozygous connexin43-deficient mice. American Journal of Physiology-Heart and Circulatory Physiology, v. 283, n. 4, p. H1740-H1742, 2002.
SEVERS, Nicholas J. et al. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovascular research, v. 80, n. 1, p. 9-19, 2008.
SEVERS, Nicholas J. et al. Remodelling of gap junctions and connexin expression in heart disease. Biochimica et Biophysica Acta (BBA)-Biomembranes, v. 1662, n. 1-2, p. 138-148, 2004.
SORGEN, Paul et al. Protein–protein interactions with connexin 43: regulation and function. International journal of molecular sciences, v. 19, n. 5, p. 1428, 2018.
SPLITT, M. Penman; BURN, J.; GOODSHIP, J. Connexin43 mutations in sporadic and familial defects of laterality. The New England journal of medicine, v. 333, n. 14, p. 941; author reply 941, 1995.
SPRAY, DAVID C.; BURT, JANIS M. Structure-activity relations of the cardiac gap junction channel. American Journal of Physiology-Cell Physiology, v. 258, n. 2, p. C195-C205, 1990.
SRIDHAR, S.; CLAYTON, Richard H. Fibroblast mediated dynamics in diffusively uncoupled myocytes: a simulation study using 2-cell motifs. Scientific Reports, v. 14, n. 1, p. 4493, 2024.
UNGER, Vinzenz M. et al. Three-dimensional structure of a recombinant gap junction membrane channel. Science, v. 283, n. 5405, p. 1176-1180, 1999.
VAN DER VELDEN, Huub MW; JONGSMA, Habo J. Cardiac gap junctions and connexins: their role in atrial fibrillation and potential as therapeutic targets. Cardiovascular research, v. 54, n. 2, p. 270-279, 2002.
VAN VEEN, Toon AB; VAN RIJEN, Harold VM; OPTHOF, Tobias. Cardiac gap junction channels: modulation of expression and channel properties. Cardiovascular research, v. 51, n. 2, p. 217-229, 2001.
WANG, Li-Jie et al. Enhanced expression of Cx43 and gap junction communication in vascular smooth muscle cells of spontaneously hypertensive rats. Molecular Medicine Reports, v. 14, n. 5, p. 4083-4090, 2016.
WANG, Yijie et al. Fibroblasts in heart scar tissue directly regulate cardiac excitability and arrhythmogenesis. Science, v. 381, n. 6665, p. 1480-1487, 2023.
WEIDMANN, Silvio. The electrical constants of Purkinje fibres. The Journal of physiology, v. 118, n. 3, p. 348, 1952.
WHITE, Thomas W.; PAUL, David L. Genetic diseases and gene knockouts reveal diverse connexin functions. Annual review of physiology, v. 61, n. 1, p. 283-310, 1999.
WILLECKE, Klaus et al. Structural and functional diversity of connexin genes in the mouse and human genome. 2002.
WIT, Andrew L.; PETERS, Nicholas S. The role of gap junctions in the arrhythmias of ischemia and infarction. Heart Rhythm, v. 9, n. 2, p. 308-311, 2012.
XU, Qin et al. Gating of connexin 43 gap junctions by a cytoplasmic loop calmodulin binding domain. American Journal of Physiology-Cell Physiology, v. 302, n. 10, p. C1548-C1556, 2012.
YA, Jing et al. Heart defects in connexin43-deficient mice. Circulation research, v. 82, n. 3, p. 360-366, 1998.
YAMADA, Kathryn A. et al. Up‐regulation of connexin45 in heart failure. Journal of cardiovascular electrophysiology, v. 14, n. 11, p. 1205-1212, 2003.
YASARBAS, S. Suheda et al. Connexins in epidermal health and diseases: insights into their mutations, implications, and therapeutic solutions. Frontiers in Physiology, v. 15, p. 1346971, 2024.
YE, Zu-Cheng et al. Functional hemichannels in astrocytes: a novel mechanism of glutamate release. Journal of Neuroscience, v. 23, n. 9, p. 3588-3596, 2003.
YEAGER, Mark; UNGER, Vinzenz M.; FALK, Matthias M. Synthesis, assembly and structure of gap junction intercellular channels. Current opinion in structural biology, v. 8, n. 4, p. 517-524, 1998.
YOKOTA, Tomohiro et al. Type V collagen in scar tissue regulates the size of scar after heart injury. Cell, v. 182, n. 3, p. 545-562. e23, 2020.YUE, Yuankun et al. The relative order of mKATP channels, free radicals and p38 MAPK in preconditioning's protective pathway in rat heart. Cardiovascular Research, v. 55, n. 3, p. 681-689, 2002.
ZEITZ, Michael J.; SMYTH, James W. Gap junctions and ageing. In: Biochemistry and Cell Biology of Ageing: Part III Biomedical Science. Cham: Springer International Publishing, 2023. p. 113-137.
ZHANG, Meng; WANG, Zhen-Zhen; CHEN, Nai-Hong. Connexin 43 Phosphorylation: Implications in Multiple Diseases. Molecules, v. 28, n. 13, p. 4914, 2023.
ZHANG, Shan-Shan et al. A micropatterning approach for imaging dynamic Cx43 trafficking to cell–cell borders. FEBS letters, v. 588, n. 8, p. 1439-1445, 2014.
ZONG, Yan-Jun et al. Cytomembrane trafficking pathways of Connexin 26, 30, and 43. International Journal of Molecular Sciences, v. 24, n. 12, p. 10349, 2023.
ZU, Lingyun et al. Connexin43 and myocardial ischemia-reperfusion injury. Cardiovascular & Haematological Disorders-Drug Targets (Formerly Current Drug Targets-Cardiovascular & Hematological Disorders), v. 18, n. 1, p. 14-16, 2018.
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