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Deletion of the last five C-terminal amino acid residues of connexin43 leads to lethal ventricular arrhythmias in mice without affecting coupling via gap junction channels

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Abstract

The cardiac intercalated disc harbors mechanical and electrical junctions as well as ion channel complexes mediating propagation of electrical impulses. Cardiac connexin43 (Cx43) co-localizes and interacts with several of the proteins located at intercalated discs in the ventricular myocardium. We have generated conditional Cx43D378stop mice lacking the last five C-terminal amino acid residues, representing a binding motif for zonula occludens protein-1 (ZO-1), and investigated the functional consequences of this mutation on cardiac physiology and morphology. Newborn and adult homozygous Cx43D378stop mice displayed markedly impaired and heterogeneous cardiac electrical activation properties and died from severe ventricular arrhythmias. Cx43 and ZO-1 were co-localized at intercalated discs in Cx43D378stop hearts, and the Cx43D378stop gap junction channels showed normal coupling properties. Patch clamp analyses of isolated adult Cx43D378stop cardiomyocytes revealed a significant decrease in sodium and potassium current densities. Furthermore, we also observed a significant loss of Nav1.5 protein from intercalated discs in Cx43D378stop hearts. The phenotypic lethality of the Cx43D378stop mutation was very similar to the one previously reported for adult Cx43 deficient (Cx43KO) mice. Yet, in contrast to Cx43KO mice, the Cx43 gap junction channel was still functional in the Cx43D378stop mutant. We conclude that the lethality of Cx43D378stop mice is independent of the loss of gap junctional intercellular communication, but most likely results from impaired cardiac sodium and potassium currents. The Cx43D378stop mice reveal for the first time that Cx43 dependent arrhythmias can develop by mechanisms other than impairment of gap junction channel function.

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Acknowledgments

This work was supported by Grants of the German Research Foundation [Wi270/32-1 and SFB 645, B2 to K.W.; FL 276/3-3 to B.K.F. and P.S.], the National Institutes of Health [R01 HL106632-01, R01 GM57691-13 to M.D.; R01NS072238, RO1HL084464 to F.F.B., as well as NIH HL084583, HL083422 to P J M], the Leducq Foundation to M.D., as well as the American Heart Association and the Saving Tiny Hearts Society to P.J.M.I.L. gratefully acknowledges a PhD stipend of the Jürgen-Manchot-Foundation. We thank Melanie Jokwitz and Christine Siegmund for excellent technical assistance and blastocyst injections.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Life and Medical Sciences (LIMES) Institute, Molecular Genetics, University of Bonn, Carl-Troll-Str. 31, 53115, Bonn, Germany

    Indra Lübkemeier, Marina Frank & Klaus Willecke

  2. Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany

    Robert Pascal Requardt

  3. Leon H. Charney Division of Cardiology, New York University Medical School, New York, NY, USA

    Xianming Lin, Halina Chkourko & Mario Delmar

  4. Institute of Physiology I, Life and Brain Center, University of Bonn, Bonn, Germany

    Philipp Sasse, Daniela Malan & Bernd K. Fleischmann

  5. Institute of Medicine-Cardiology, University of Bonn, Bonn, Germany

    René Andrié & Jan Wilko Schrickel

  6. Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, USA

    Feliksas F. Bukauskas

  7. Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Jung-Sun Kim

  8. Institute of Cellular Neurosciences, University of Bonn, Bonn, Germany

    Jiong Zhang

  9. Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany

    Angela Wirth & Stefan Offermanns

  10. Department of Biological Sciences, Rutgers University, Newark, NJ, USA

    Radoslaw Dobrowolski

  11. Departments of Internal Medicine and Physiology, Dorothy M. Davis Heart and Lung Research Institute, Ohio State University Medical Center, Columbus, OH, USA

    Peter J. Mohler

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  1. Indra Lübkemeier
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Correspondence to Klaus Willecke.

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M. Delmar and K. Willecke contributed equally to this work.

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Lübkemeier, I., Requardt, R.P., Lin, X. et al. Deletion of the last five C-terminal amino acid residues of connexin43 leads to lethal ventricular arrhythmias in mice without affecting coupling via gap junction channels. Basic Res Cardiol 108, 348 (2013). https://doi.org/10.1007/s00395-013-0348-y

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