Is there a role for remodeled connexins in AF? No simple answers

Abstract

Gap junctions provide direct cytoplasmic continuity between cells forming a low resistivity barrier to electrical propagation. As such, aberrant regulation of these low resistive conduits has been blamed for electrical conduction disorders in diseased myocardium. While there is a plethora of evidence that abnormalities in gap junctional communication underlie many forms of ventricular arrhythmias, the role of gap junctions in atrial conduction disorders has been less well studied. The atria are the most heterogeneous cardiac structures in terms of the gap junction proteins, connexins (Cx), which are present. Cx40 is the primary, or most abundant, gap junction protein in atria although Cx43 is also abundantly expressed. Cx45 is also expressed in atria, although at low levels. This heterogeneity in connexins leads to a complexity that makes understanding the role of cell coupling in conduction disorders and arrhythmogenesis difficult. In this review we focus on what is known about atrial connexins and their role in atrial fibrillation but also on the challenges presented in understanding the complex interplay between the individual connexin isoforms.

Figure 1

Topology of the three atrial connexin proteins. All have four transmembrane domains and an intracellular amino, loop, and carboxyl domain. Areas of red indicate alpha helices while green regions are the beta sheets within each molecule. Conserved prolines are seen in black. Areas of highest divergence are within the cytoplasmic domains of the connexins [43].

Figure 2

Table showing the possible combinations which form functional channels. All combinations of Cx40,Cx43, and Cx45 potentially form functional channels within the atrium.