Function Study of Atrial Fibrillation-Linked Connexin Mutants and Heterotypic Docking Compatibility of Cardiac Connexins
Gap junctions are critical for the propagation of action potentials in the heart. Many autosomal dominant Cx40 mutations have been linked to atrial fibrillation (AF) and have showed GJ impairments. However, others such as L221I and V85I showed apparently no GJ impairments. Cells expressing L221I or V85I alone showed increased propidium iodide uptake, which was also the case for cells co-expressing L221I and wildtype Cx40, suggesting increased hemichannel opening probability. A novel AF-linked Cx45 mutant (M235L) was found to impair GJ function. These alterations in hemichannel or GJ function might play a role in promoting AF. The atria express Cx40 and Cx43 abundantly with low levels of Cx45, and may form heterotypic GJs. However, wildtype heterotypic Cx40/Cx43 or Cx40/Cx45 GJs were not functional, unless a designed Cx40 structural variant (D55N) was used, suggesting these heterotypic GJs are unlikely to mediate coupling in the native heart.
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