Tags

Type your tag names separated by a space and hit enter

Fate of connexin43 in cardiac tissue harbouring a disease-linked connexin43 mutant.
Cardiovasc Res. 2008 Dec 01; 80(3):385-95.CR

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 (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.

Authors+Show Affiliations

Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18678643

Citation

Manias, Janet L., et al. "Fate of Connexin43 in Cardiac Tissue Harbouring a Disease-linked Connexin43 Mutant." Cardiovascular Research, vol. 80, no. 3, 2008, pp. 385-95.
Manias JL, Plante I, Gong XQ, et al. Fate of connexin43 in cardiac tissue harbouring a disease-linked connexin43 mutant. Cardiovasc Res. 2008;80(3):385-95.
Manias, J. L., Plante, I., Gong, X. Q., Shao, Q., Churko, J., Bai, D., & Laird, D. W. (2008). Fate of connexin43 in cardiac tissue harbouring a disease-linked connexin43 mutant. Cardiovascular Research, 80(3), 385-95. https://doi.org/10.1093/cvr/cvn203
Manias JL, et al. Fate of Connexin43 in Cardiac Tissue Harbouring a Disease-linked Connexin43 Mutant. Cardiovasc Res. 2008 Dec 1;80(3):385-95. PubMed PMID: 18678643.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fate of connexin43 in cardiac tissue harbouring a disease-linked connexin43 mutant. AU - Manias,Janet L, AU - Plante,Isabelle, AU - Gong,Xiang-Qun, AU - Shao,Qing, AU - Churko,Jared, AU - Bai,Donglin, AU - Laird,Dale W, Y1 - 2008/08/04/ PY - 2008/8/6/pubmed PY - 2009/3/11/medline PY - 2008/8/6/entrez SP - 385 EP - 95 JF - Cardiovascular research JO - Cardiovasc. Res. VL - 80 IS - 3 N2 - 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. SN - 1755-3245 UR - https://www.unboundmedicine.com/medline/citation/18678643/Fate_of_connexin43_in_cardiac_tissue_harbouring_a_disease_linked_connexin43_mutant_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1093/cvr/cvn203 DB - PRIME DP - Unbound Medicine ER -