Fate of connexin43 in cardiac tissue harbouring a disease-linked connexin43 mutant

Manias, Janet L; Plante, Isabelle ORCID: https://orcid.org/0000-0003-2080-6450; Gong, Xiang-Qun; Shao, Qing; Churko, Jared; Bai, Donglin et Laird, Dale W (2008). Fate of connexin43 in cardiac tissue harbouring a disease-linked connexin43 mutant Cardiovascular Research , vol. 80 , nº 3. pp. 385-395. DOI: 10.1093/cvr/cvn203.

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Résumé

AIMS: More than 40 mutations in the GJA1 gene encoding connexin43 (Cx43) have been linked to oculodentodigital dysplasia (ODDD), a pleiotropic, autosomal dominant disorder. We hypothesized that even with a significant reduction in the levels of Cx43 in a mutant mouse model of ODDD (Gja1(Jrt/+)) harbouring a G60S mutation (Cx43(G60S)), cardiomyocyte function may only be moderately compromised given that a majority of mutant mice typically survive.

METHODS AND RESULTS:Western blotting and quantitative reverse transcriptase-polymerase chain reaction in conjunction with immunofluorescence were used to assess the expression and localization of Cx43 in hearts and cultured cardiomyocytes from wild-type and Gja1(Jrt/+) mice. Dye-coupling and dual whole cell patch-clamp recordings were also used to assess the gap junction channel status in cultured cardiomyocytes from wild-type and mutant mice. Cardiac tissue from adult Gja1(Jrt/+) mice revealed a 60-80% reduction in Cx43 protein with a preferential loss of the highly phosphorylated forms of Cx43. Compensation via the up-regulation of Cx40 or Cx45 was not observed. Immunofluorescent analysis of cultured cardiomyocytes revealed a trafficking defect, with a decrease in Cx43 plaques and a large population of Cx43 being retained in the Golgi apparatus. However, cultured cardiomyocytes from mutant mice remained beating with a 50% decrease in coupling conductance.

CONCLUSION: These results suggest that the Cx43(G60S) mutant impairs normal trafficking and function of co-expressed Cx43 with no dramatic effect on cardiomyocyte function, suggesting that Cx43 is biosynthesized in excess of an essential need.

Type de document:	Article
Mots-clés libres:	Connexin43; Gap junctions; Cardiomyocytes; Mutant mice; Disease
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	02 août 2024 14:11
Dernière modification:	02 août 2024 14:11
URI:	https://espace.inrs.ca/id/eprint/14943

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