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Altered conductance and permeability of Cx40 mutations associated with atrial fibrillation

Ana Santa Cruz1, Gülistan Meşe1, Laima Valiuniene1

  • 1Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11792.

The Journal of General Physiology
|October 28, 2015
PubMed

Insights

Mutant connexin40 (Cx40) proteins associated with atrial fibrillation alter gap junction channel properties. These biophysical changes in Cx40 mutants may contribute to cardiac arrhythmias like reentry.

Area of Science:

  • Cardiovascular Biology
  • Molecular Biophysics
  • Genetics

Background:

  • Gap junctions, formed by connexin proteins, are crucial for rapid electrical impulse propagation in the heart.
  • Mutations in connexin40 (Cx40), the main component of atrial gap junctions, are linked to atrial fibrillation.
  • The specific biophysical alterations of Cx40 mutants contributing to arrhythmias are not fully understood.

Purpose of the Study:

  • To investigate the biophysical properties of three Cx40 mutants (A96S, M163V, G38D) associated with atrial fibrillation.
  • To compare the unitary conductance, ion permeability, and dye permeability of mutant Cx40 channels to wild-type (WT) Cx40.
  • To elucidate how these altered channel properties may contribute to cardiac arrhythmias.

Main Methods:

  • Transiently transfected HeLa and N2A cells were used to express WT Cx40 and its mutants.
  • Macroscopic and unitary conductances were measured.
  • Permeability assays using Lucifer yellow (anionic dye) and ethidium bromide (cationic dye) relative to K+ were performed.

Main Results:

  • All Cx40 mutants formed functional channels with comparable macroscopic conductances and voltage dependences to WT Cx40.
  • The G38D mutant exhibited significantly higher unitary conductance and increased Lucifer yellow permeability compared to WT Cx40.
  • The M163V and G38D mutants showed altered ion selectivity, with increased ethidium bromide permeability, while G38D showed reduced permeability, suggesting changes in channel pore characteristics.

Conclusions:

  • Mutations in Cx40 associated with atrial fibrillation alter both conductive and permeability properties of gap junction channels.
  • These biophysical changes in Cx40 mutants may underlie the mechanisms of reentry arrhythmias.
  • Cx40-mediated electrical and biochemical coupling is essential for normal cardiac function, and its disruption by mutations can lead to disease.

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