title: 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.
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.
authors.affiliation: Life and Medical Sciences (LIMES) Institute, Molecular Genetics, University of Bonn, Carl-Troll-Str. 31, 53115, Bonn, Germany.
authors.forename: Indra
authors.initials: I
authors.lastname: Lübkemeier
authors.forename: Robert Pascal
authors.initials: RP
authors.lastname: Requardt
authors.forename: Xianming
authors.initials: X
authors.lastname: Lin
authors.forename: Philipp
authors.initials: P
authors.lastname: Sasse
authors.forename: René
authors.initials: R
authors.lastname: Andrié
authors.forename: Jan Wilko
authors.initials: JW
authors.lastname: Schrickel
authors.forename: Halina
authors.initials: H
authors.lastname: Chkourko
authors.forename: Feliksas F
authors.initials: FF
authors.lastname: Bukauskas
authors.forename: Jung-Sun
authors.initials: JS
authors.lastname: Kim
authors.forename: Marina
authors.initials: M
authors.lastname: Frank
authors.forename: Daniela
authors.initials: D
authors.lastname: Malan
authors.forename: Jiong
authors.initials: J
authors.lastname: Zhang
authors.forename: Angela
authors.initials: A
authors.lastname: Wirth
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Dobrowolski
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Fleischmann
authors.forename: Mario
authors.initials: M
authors.lastname: Delmar
authors.forename: Klaus
authors.initials: K
authors.lastname: Willecke
mesh_terms: D000200:Action Potentials; D000367:Age Factors; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018031:Connexin 43 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015716:Electrocardiography, Ambulatory; D056149:Epicardial Mapping; D017629:Gap Junctions / Q000378:metabolism*; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010641:Phenotype; D013686:Telemetry; D013997:Time Factors; D014162:Transfection; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D018031:Connexin 43; C543076:GJA1 protein, mouse; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein
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