Connexin diversity in the heart: insights from transgenic mouse models

Cardiac conduction is mediated by gap junction channels that are formed by connexin (Cx) protein subunits. The connexin family of proteins consists of more than 20 members varying in their biophysical properties and ability to combine with other connexins into heteromeric gap junction channels. The mammalian heart shows regional differences both in connexin expression profile and in degree of electrical coupling. The latter reflects functional requirements for conduction velocity which needs to be low in the sinoatrial and atrioventricular nodes and high in the ventricular conduction system. Over the past 20 years knowledge of the biology of gap junction channels and their role in the genesis of cardiac arrhythmias has increased enormously. This review focuses on the insights gained from transgenic mouse models. The mouse heart expresses Cx30, 30.2, 37, 40, 43, 45, and 46. For these connexins a variety of knock-outs, heart-specific knock-outs, conditional knock-outs, double knock-outs, knock-ins and overexpressors has been studied. We discuss the cardiac phenotype in these models and compare Cx expression between mice and men. Mouse models have enhanced our understanding of (patho)-physiological implications of Cx diversity in the heart. In principle connexin-specific modulation of electrical coupling in the heart represents an interesting treatment strategy for cardiac arrhythmias and conduction disorders.

• Publication year

  2013

• Venue

  Frontiers in Pharmacology

• Publication date

  2013-05-03

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.3389/fphar.2013.00081PMID 23818881PMCID 3694209
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Absence of venous valves in mice lacking Connexin37.

  2013cited by this paper
• Mitochondrial connexin 43 impacts on respiratory complex I activity and mitochondrial oxygen consumption

  2012cited by this paper
• The effect of connexin40 deficiency on ventricular conduction system function during development.

  2012cited by this paper
• Connexin43 ablation in foetal atrial myocytes decreases electrical coupling, partner connexins, and sodium current.

  2012cited by this paper
• Actin Cytoskeleton Rest Stops Regulate Anterograde Traffic of Connexin 43 Vesicles to the Plasma Membrane

  2012influential reference
• Cardiac connexins, mutations and arrhythmias

  2012cited by this paper
• Connexin45 Provides Optimal Atrioventricular Nodal Conduction in the Adult Mouse Heart

  2012influential reference
• Reduced Cx43 Expression Triggers Increased Fibrosis Due to Enhanced Fibroblast Activity

  2012cited by this paper
• UvA-DARE ( Digital Academic Repository ) Role of Tbx 3 in conduction system development

  2012cited by this paper
• The molecular mechanisms of gap junction remodeling.

  2012cited by this paper
• TBX5 drives Scn5a expression to regulate cardiac conduction system function.

  2012cited by this paper
• Manipulating Connexin Communication Channels: Use of Peptidomimetics and the Translational Outputs

  2012cited by this paper
• The Noncanonical Functions of Cx43 in the Heart

  2012cited by this paper
• The role of gap junctions in the arrhythmias of ischemia and infarction.

  2012cited by this paper
• Cardiac electrophysiology in mice: a matter of size

  2012cited by this paper
• Reduced heterogeneous expression of Cx43 results in decreased Nav1.5 expression and reduced sodium current that accounts for arrhythmia vulnerability in conditional Cx43 knockout mice.

  2012cited by this paper
• Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-A combined murine and human study

  2012cited by this paper
• study on

  2012influential reference
• Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury

  2012cited by this paper
• Residual Cx45 and its relationship to Cx43 in murine ventricular myocardium

  2011cited by this paper
• Molecular Analysis of Patterning of Conduction Tissues in the Developing Human Heart

  2011cited by this paper
• Pharmacological modulation of connexin‐formed channels in cardiac pathophysiology

  2011cited by this paper
• Adrenergic control of cardiac gap junction function and expression

  2011cited by this paper
• Defective Tbx2-dependent patterning of the atrioventricular canal myocardium causes accessory pathway formation in mice.

  2011cited by this paper
• Increased Cell–Cell Coupling Increases Infarct Size and Does not Decrease Incidence of Ventricular Tachycardia in Mice

  2011cited by this paper
• Molecular architecture of the human specialised atrioventricular conduction axis.

  2011influential reference
• Phosphatase-Resistant Gap Junctions Inhibit Pathological Remodeling and Prevent Arrhythmias

  2011cited by this paper
• Atrial tachycardia/fibrillation in the connexin 43 G60S mutant (Oculodentodigital dysplasia) mouse.

  2011cited by this paper
• Notch signaling regulates murine atrioventricular conduction and the formation of accessory pathways.

  2011cited by this paper
• Transcriptional Suppression of Connexin43 by TBX18 Undermines Cell-Cell Electrical Coupling in Postnatal Cardiomyocytes

  2011cited by this paper
• Connexin40 and connexin43 determine gating properties of atrial gap junction channels.

  2010cited by this paper
• Remodeling of cardiac fibroblasts following myocardial infarction results in increased gap junction intercellular communication.

  2010cited by this paper
• Cardiac conduction is required to preserve cardiac chamber morphology

  2010cited by this paper
• Peptides targeting gap junctional structures.

  2010cited by this paper
• Cx30 in the sinus node of murine heart: just one connexin more, or more? Evidence for a construction principle?

  2010cited by this paper
• Neuronal connexin-36 can functionally replace connexin-45 in mouse retina but not in the developing heart

  2010influential reference
• Effects of substitution of Cx43 by Cx32 on myocardial energy metabolism, tolerance to ischaemia and preconditioning protection

  2010cited by this paper
• Diversity and properties of connexin gap junction channels.

  2010influential reference
• Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice.

  2010cited by this paper
• Connexin 30 is expressed in the mouse sino-atrial node and modulates heart rate.

  2010cited by this paper
• Reduced expression of Cx43 attenuates ventricular remodeling after myocardial infarction via impaired TGF-beta signaling.

  2010cited by this paper
• Modeling electrical activity of myocardial cells incorporating the effects of ephaptic coupling

  2010influential reference
• Cx43 CT domain influences infarct size and susceptibility to ventricular tachyarrhythmias in acute myocardial infarction.

  2009cited by this paper
• Connexin43 phosphorylation: structural changes and biological effects.

  2009cited by this paper
• Connexin-Caused Genetic Diseases and Corresponding Mouse Models

  2009cited by this paper
• Molecular Architecture of the Human Sinus Node: Insights Into the Function of the Cardiac Pacemaker

  2009cited by this paper
• Connexin43 in cardiomyocyte mitochondria contributes to mitochondrial potassium uptake.

  2009cited by this paper
• Human connexin31.9, unlike its orthologous protein connexin30.2 in the mouse, is not detectable in the human cardiac conduction system.

  2009cited by this paper
• Normal impulse propagation in the atrioventricular conduction system of Cx30.2/Cx40 double deficient mice.

  2009cited by this paper
• Presence of connexin 43 in subsarcolemmal, but not in interfibrillar cardiomyocyte mitochondria

  2009cited by this paper
• Combined reduction of intercellular coupling and membrane excitability differentially affects transverse and longitudinal cardiac conduction.

  2009cited by this paper
• Cx30.2 enhancer analysis identifies Gata4 as a novel regulator of atrioventricular delay

  2009cited by this paper
• Formation of the Sinus Node Head and Differentiation of Sinus Node Myocardium Are Independently Regulated by Tbx18 and Tbx3

  2009cited by this paper
• Connexin40 Imparts Conduction Heterogeneity to Atrial Tissue

  2008influential reference
• Mitochondrial connexin43 as a new player in the pathophysiology of myocardial ischaemia-reperfusion injury.

  2008cited by this paper
• Coexpression of Connexin45 with Connexin43 Decreases Gap Junction Size

  2008cited by this paper
• Fate of connexin43 in cardiac tissue harbouring a disease-linked connexin43 mutant.

  2008cited by this paper
• Connexin 43 Expression Delineates Two Discrete Pathways in the Human Atrioventricular Junction

  2008influential reference
• The conditional connexin43G138R mouse mutant represents a new model of hereditary oculodentodigital dysplasia in humans.

  2008influential reference
• Decreased connexin43 expression in the mouse heart potentiates pacing-induced remodeling of repolarizing currents

  2008cited by this paper
• Transcription Factor Tbx3 Is Required for the Specification of the Atrioventricular Conduction System

  2008cited by this paper
• Cx30.2 can form heteromeric gap junction channels with other cardiac connexins.

  2008cited by this paper
• Short-term pacing in the mouse alters cardiac expression of connexin43

  2008cited by this paper
• Electrical remodeling contributes to complex tachyarrhythmias in connexin43‐deficient mouse hearts

  2008cited by this paper
• A Study on

  2008cited by this paper
• Fate of connexin 43 in cardiac tissue harbouring a disease-linked connexin 43 mutant

  2008cited by this paper
• C-Terminal Truncation of Connexin43 Changes Number, Size, and Localization of Cardiac Gap Junction Plaques

  2007cited by this paper
• Propagated Endothelial Ca 2 Waves and Arteriolar Dilation In Vivo Measurements in Cx 40 BAC – GCaMP 2 Transgenic Mice

  2007cited by this paper
• The modulatory effects of connexin 43 on cell death/survival beyond cell coupling.

  2007cited by this paper
• Gap junctional complexes: from partners to functions.

  2007influential reference
• Replacement of connexin43 by connexin26 in transgenic mice leads to dysfunctional reproductive organs and slowed ventricular conduction in the heart

  2007cited by this paper
• Gap junction remodeling and cardiac arrhythmogenesis in a murine model of oculodentodigital dysplasia

  2007influential reference
• Molecular basis of voltage dependence of connexin channels: an integrative appraisal.

  2007cited by this paper
• Propagated Endothelial Ca2+ Waves and Arteriolar Dilation In Vivo: Measurements in Cx40BAC-GCaMP2 Transgenic Mice

  2007cited by this paper
• Cardiac morphogenetic defects and conduction abnormalities in mice homozygously deficient for connexin40 and heterozygously deficient for connexin45.

  2006cited by this paper
• Connexin30.2 containing gap junction channels decelerate impulse propagation through the atrioventricular node.

  2006cited by this paper
• Differentiation of cardiac Purkinje fibers requires precise spatiotemporal regulation of Nkx2‐5 expression

  2006cited by this paper
• Connexin31 cannot functionally replace connexin43 during cardiac morphogenesis in mice

  2006cited by this paper
• Effects of the Gap Junction Modifier Rotigaptide (ZP123) on Atrial Conduction and Vulnerability to Atrial Fibrillation

  2006cited by this paper
• Distinct cardiac malformations caused by absence of connexin 43 in the neural crest and in the non-crest neural tube

  2006cited by this paper
• Overexpression of cardiac connexin45 increases susceptibility to ventricular tachyarrhythmias in vivo.

  2006cited by this paper
• Relative Contributions of Connexins 40 and 43 to Atrial Impulse Propagation in Synthetic Strands of Neonatal and Fetal Murine Cardiomyocytes

  2006cited by this paper
• Larger Cell Size in Rabbits With Heart Failure Increases Myocardial Conduction Velocity and QRS Duration

  2006cited by this paper
• Cardiac ischemia and uncoupling: gap junctions in ischemia and infarction.

  2006cited by this paper
• Properties of mouse connexin 30.2 and human connexin 31.9 hemichannels: implications for atrioventricular conduction in the heart.

  2006cited by this paper
• Primordial germ cell deficiency in the connexin 43 knockout mouse arises from apoptosis associated with abnormal p53 activation

  2006influential reference
• Cardiomyocyte-restricted deletion of connexin43 during mouse development.

  2006cited by this paper
• Normal embryonic development and cardiac morphogenesis in mice with Wnt1‐Cre‐mediated deletion of connexin43

  2006cited by this paper
• Altered Right Atrial Excitation and Propagation in Connexin40 Knockout Mice

  2005cited by this paper
• A Gja1 missense mutation in a mouse model of oculodentodigital dysplasia

  2005influential reference
• Atrioventricular nodal reverse facilitation in connexin40-deficient mice.

  2005cited by this paper
• Genes controlling multiple functional pathways are transcriptionally regulated in connexin43 null mouse heart.

  2005cited by this paper
• Reduced intercellular coupling leads to paradoxical propagation across the Purkinje-ventricular junction and aberrant myocardial activation.

  2005cited by this paper
• Connexin43 deficiency causes dysregulation of coronary vasculogenesis.

  2005cited by this paper
• Cardiac-Specific Loss of N-Cadherin Leads to Alteration in Connexins With Conduction Slowing and Arrhythmogenesis

  2005cited by this paper
• Dynamic model for ventricular junctional conductance during the cardiac action potential.

  2005cited by this paper
• Impaired Impulse Propagation in Scn5a-Knockout Mice: Combined Contribution of Excitability, Connexin Expression, and Tissue Architecture in Relation to Aging

  2005influential reference
• Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning.

  2005cited by this paper
• Induced Deletion of the N-Cadherin Gene in the Heart Leads to Dissolution of the Intercalated Disc Structure

  2005cited by this paper
• Focal gap junction uncoupling and spontaneous ventricular ectopy.

  2005cited by this paper

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• A versatile microfluidics platform for enhanced multi-target super-resolution microscopy

  2025cites this paper
• Brain Endothelial Gap Junction Coupling Enables Rapid Vasodilation Propagation During Neurovascular Coupling

  2025cites this paper
• Coordinated Tbx3/Tbx5 transcriptional control of the adult ventricular conduction system

  2025cites this paper
• Gap junctional and ephaptic coupling in cardiac electrical propagation: homocellular and heterocellular perspectives

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• Connexin‐43 remodelling and arrhythmias: hemichannels as key drivers of cardiac dysfunction

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• The Functional and Imaging Implications of Left Bundle Branch Pacing in Ischemic Cardiomyopathy

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• Myocardial expression of connexin 43 in cats with hypertrophic and restrictive cardiomyopathy phenotype

  2025cites this paper
• The horse cardiac transcriptome: Moving towards a molecular understanding of atrial fibrillation.

  2025cites this paper
• Tumor microtubes: A new potential therapeutic target for high-grade gliomas.

  2024cites this paper
• Coordinated Tbx3/Tbx5 transcriptional control of the adult ventricular conduction system

  2024cites this paper
• Knockout of the Cardiac Transcription Factor NKX2-5 Results in Stem Cell-Derived Cardiac Cells with Typical Purkinje Cell-like Signal Transduction and Extracellular Matrix Formation

  2023cites this paper
• Adapting to a new environment: postnatal maturation of the human cardiomyocyte

  2023cites this paper
• Research Progress on Natural Products' Therapeutic Effects on Atrial Fibrillation by Regulating Ion Channels

  2022cites this paper
• The IgCAM CAR Regulates Gap Junction-Mediated Coupling on Embryonic Cardiomyocytes and Affects Their Beating Frequency

  2022cites this paper
• Role of gap junctions and connexin 43 in cancerogenesis and tumor metastasis

  2022cites this paper
• Direct reprogramming of cardiomyocytes into cardiac Purkinje-like cells

  2022cites this paper
• GJA1 gene polymorphism is a genetic predictor of recurrence following pulmonary vein isolation in patients with paroxysmal atrial fibrillation.

  2022cites this paper
• Virus-induced inhibition of cardiac pacemaker channel HCN4 triggers bradycardia in human-induced stem cell system

  2022cites this paper
• Multi-chamber cardioids unravel human heart development and cardiac defects

  2022cites this paper
• Expression of connexin-43 in surgical resections of primary tumor and lymph node metastases of squamous cell carcinoma and adenocarcinoma of the lung: a retrospective study

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• Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models

  2021cites this paper
• Utility of Zebrafish Models of Acquired and Inherited Long QT Syndrome

  2021cites this paper
• Minor allele of GJA1 gene polymorphism is associated with higher heart rate during atrial fibrillation

  2021cites this paper
• AS602801 sensitizes glioma cells to temozolomide and vincristine by blocking gap junction communication between glioma cells and astrocytes

  2021cites this paper
• A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes

  2021cites this paper
• Connexin Hemichannel Inhibitors with a Focus on Aminoglycosides.

  2021cites this paper
• Cellular crosstalk in cardioprotection: where and when do reactive oxygen species play a role?

  2021cites this paper
• Maturing heart muscle cells: Mechanisms and transcriptomic insights

  2021cites this paper
• Cardiac Biomarkers and Autoantibodies in Endurance Athletes: Potential Similarities with Arrhythmogenic Cardiomyopathy Pathogenic Mechanisms

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• Molecular Profiling of the Cardiac Conduction System: the Dawn of a New Era

  2021cites this paper
• Conductance heterogeneities induced by multistability in the dynamics of coupled cardiac gap junctions.

  2021cites this paper
• Connecting different heart diseases through intercellular communication

  2021cites this paper
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  2021cites this paper
• Cytoprotective and cytofunctional effect of polyanionic polysaccharide alginate and gelatin microspheres on rat cardiac cells.

  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2019cites this paper
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  2019cites this paper
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  2018cites this paper
• Ventricular pro-arrhythmic phenotype, arrhythmic substrate, ageing and mitochondrial dysfunction in peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β−/−) murine hearts

  2018cites this paper
• Three-dimensional reconstruction of the intercalated disc including the intercellular junctions by applying volume scanning electron microscopy

  2018cites this paper
• Murine Electrophysiological Models of Cardiac Arrhythmogenesis.

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• MED12 regulates a transcriptional network of calcium-handling genes in the heart.

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• Unmasking the molecular link between arrhythmogenic cardiomyopathy and Brugada syndrome

  2017cites this paper
• Mechanisms of Electrical Activation and Conduction in the Gastrointestinal System: Lessons from Cardiac Electrophysiology

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• Altered Connexin 43 and Connexin 45 protein expression in the heart as a function of social and environmental stress in the prairie vole

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• Intracellular Cleavage of the Cx43 C-Terminal Domain by Matrix-Metalloproteases: A Novel Contributor to Inflammation?

  2015cites this paper
• Human Connexin43E42K Mutation From a Sudden Infant Death Victim Leads to Impaired Ventricular Activation and Neonatal Death in Mice

  2015cites this paper
• Localization and quantitative analysis of Cx43 in porcine oocytes during in vitro maturation

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• Overexpression of myocardin induces partial transdifferentiation of human‐induced pluripotent stem cell‐derived mesenchymal stem cells into cardiomyocytes

  2014cites this paper
• Mix and match: Investigating heteromeric and heterotypic gap junction channels in model systems and native tissues

  2014cites this paper
• Congenital Heart Diseases and Biotechnology: Connecting by Connexin

  2014cites this paper
• Connexins in lymphatic vessel physiology and disease

  2014cites this paper
• Structure and function of gap junction proteins: role of gap junction proteins in embryonic heart development.

  2014influential citation
• Gap junction modulation and its implications for heart function

  2014cites this paper
• Mind the gap! Connexins and pannexins in physiology, pharmacology and disease

  2013cites this paper