Ultrastructure and regulation of lateralized connexin43 in the failing heart

Circ Res. 2010 Apr 2;106(6):1153-63. doi: 10.1161/CIRCRESAHA.108.182147. Epub 2010 Feb 18.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autophagy
  • Connexin 43 / genetics
  • Connexin 43 / metabolism*
  • Disease Models, Animal
  • Dogs
  • Gap Junctions / metabolism*
  • Gap Junctions / ultrastructure*
  • HeLa Cells
  • Heart Failure / metabolism*
  • Heart Failure / pathology*
  • Heart Ventricles / metabolism
  • Heart Ventricles / ultrastructure
  • Humans
  • Membrane Microdomains / metabolism
  • Membrane Microdomains / ultrastructure
  • Microscopy, Confocal
  • Microscopy, Electron, Transmission
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Myocardium / metabolism*
  • Myocardium / ultrastructure*
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Fusion Proteins / metabolism
  • Transfection


  • Connexin 43
  • GJA1 protein, human
  • Microtubule-Associated Proteins
  • Recombinant Fusion Proteins