Ultrastructure and regulation of lateralized connexin43 in the failing heart

Geoffrey G. Hesketh, Manish H. Shah, Victoria L. Halperin, Carol A. Cooke, Fadi G. Akar, Timothy E. Yen, David A. Kass, Carolyn E. MacHamer, Jennifer E. Van Eyk, Gordon F. Tomaselli

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

RATIONALE: Gap junctions mediate cell-to-cell electric coupling of cardiomyocytes. The primary gap junction protein in the working myocardium, connexin43 (Cx43), exhibits increased localization at the lateral membranes of cardiomyocytes in a variety of heart diseases, although the precise location and function of this population is unknown. OBJECTIVE: To define the subcellular location of lateralized gap junctions at the light and electron microscopic level, and further characterize the biochemical regulation of gap junction turnover. METHODS AND RESULTS: By electron microscopy, we characterized gap junctions formed between cardiomyocyte lateral membranes in failing canine ventricular myocardium. These gap junctions were varied in structure and appeared to be extensively internalizing. Internalized gap junctions were incorporated into multilamellar membrane structures, with features characteristic of autophagosomes. Intracellular Cx43 extensively colocalized with the autophagosome marker GFP-LC3 when both proteins were exogenously expressed in HeLa cells, and endogenous Cx43 colocalized with GFP-LC3 in neonatal rat ventricular myocytes. Furthermore, a distinct phosphorylated form of Cx43, as well as the autophagosome-targeted form of LC3 (microtubule- associated protein light chain 3) targeted to lipid rafts in cardiac tissue, and both were increased in heart failure. CONCLUSIONS: Our data demonstrate a previously unrecognized pathway of gap junction internalization and degradation in the heart and identify a cellular pathway with potential therapeutic implications.

Original languageEnglish (US)
Pages (from-to)1153-1163
Number of pages11
JournalCirculation research
Volume106
Issue number6
DOIs
StatePublished - Apr 1 2010

Keywords

  • Autophagy
  • Connexin43
  • Gap junctions
  • Heart failure
  • Lipid rafts

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Ultrastructure and regulation of lateralized connexin43 in the failing heart'. Together they form a unique fingerprint.

  • Cite this

    Hesketh, G. G., Shah, M. H., Halperin, V. L., Cooke, C. A., Akar, F. G., Yen, T. E., Kass, D. A., MacHamer, C. E., Van Eyk, J. E., & Tomaselli, G. F. (2010). Ultrastructure and regulation of lateralized connexin43 in the failing heart. Circulation research, 106(6), 1153-1163. https://doi.org/10.1161/CIRCRESAHA.108.182147