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

Indra Lübkemeier, Robert Pascal Requardt, Xianming Lin, Philipp Sasse, René Andrié, Jan Wilko Schrickel, Halina Chkourko, Feliksas F. Bukauskas, Jung Sun Kim, Marina Frank, Daniela Malan, Jiong Zhang, Angela Wirth, Radoslaw Dobrowolski, Peter J. Mohler, Stefan Offermanns, Bernd K. Fleischmann, Mario Delmar, Klaus Willecke

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number348
JournalBasic Research in Cardiology
Volume108
Issue number3
DOIs
StatePublished - 2013

Fingerprint

Connexin 43
Gap Junctions
Cardiac Arrhythmias
Amino Acids
Zonula Occludens-1 Protein
Potassium
Sodium
Mutation
Ion Channels
Cardiac Myocytes
Myocardium
Proteins

Keywords

  • Connexin43
  • Intercalated disc
  • Na1.5
  • Zonula occludens protein-1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

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. / Lübkemeier, Indra; Requardt, Robert Pascal; Lin, Xianming; Sasse, Philipp; Andrié, René; Schrickel, Jan Wilko; Chkourko, Halina; Bukauskas, Feliksas F.; Kim, Jung Sun; Frank, Marina; Malan, Daniela; Zhang, Jiong; Wirth, Angela; Dobrowolski, Radoslaw; Mohler, Peter J.; Offermanns, Stefan; Fleischmann, Bernd K.; Delmar, Mario; Willecke, Klaus.

In: Basic Research in Cardiology, Vol. 108, No. 3, 348, 2013.

Research output: Contribution to journalArticle

Lübkemeier, I, Requardt, RP, Lin, X, Sasse, P, Andrié, R, Schrickel, JW, Chkourko, H, Bukauskas, FF, Kim, JS, Frank, M, Malan, D, Zhang, J, Wirth, A, Dobrowolski, R, Mohler, PJ, Offermanns, S, Fleischmann, BK, Delmar, M & Willecke, K 2013, '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 Research in Cardiology, vol. 108, no. 3, 348. https://doi.org/10.1007/s00395-013-0348-y
Lübkemeier, Indra ; Requardt, Robert Pascal ; Lin, Xianming ; Sasse, Philipp ; Andrié, René ; Schrickel, Jan Wilko ; Chkourko, Halina ; Bukauskas, Feliksas F. ; Kim, Jung Sun ; Frank, Marina ; Malan, Daniela ; Zhang, Jiong ; Wirth, Angela ; Dobrowolski, Radoslaw ; Mohler, Peter J. ; Offermanns, Stefan ; Fleischmann, Bernd K. ; Delmar, Mario ; Willecke, Klaus. / 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. In: Basic Research in Cardiology. 2013 ; Vol. 108, No. 3.
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AU - Lübkemeier, Indra

AU - Requardt, Robert Pascal

AU - Lin, Xianming

AU - Sasse, Philipp

AU - Andrié, René

AU - Schrickel, Jan Wilko

AU - Chkourko, Halina

AU - Bukauskas, Feliksas F.

AU - Kim, Jung Sun

AU - Frank, Marina

AU - Malan, Daniela

AU - Zhang, Jiong

AU - Wirth, Angela

AU - Dobrowolski, Radoslaw

AU - Mohler, Peter J.

AU - Offermanns, Stefan

AU - Fleischmann, Bernd K.

AU - Delmar, Mario

AU - Willecke, Klaus

PY - 2013

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N2 - 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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