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

Janet L. Manias, Isabelle Plante, Xiang Qun Gong, Qing Shao, Jared Churko, Donglin Bai, Dale W. Laird

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

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 (Gja1Jrt/+) harbouring a G60S mutation (Cx43G60S), 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 Gja1Jrt/+ 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 Gja1Jrt/+ 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 Cx43G60S 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.

Original languageEnglish (US)
Pages (from-to)385-395
Number of pages11
JournalCardiovascular research
Volume80
Issue number3
DOIs
StatePublished - Dec 2008
Externally publishedYes

Keywords

  • Cardiomyocytes
  • Connexin43
  • Disease
  • Gap junctions
  • Mutant mice

ASJC Scopus subject areas

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

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