The perinexus: A new feature of Cx43 gap junction organization

The intercellular propagation of action potential is a necessary prerequisite of cardiac function. It is widely held that this is achieved by direct coupling between myocytes mediated by gap junctions – aggregates of cell-to-cell connexon channels. Connexons in the plasma membrane of cardiomyocytes not docked within gap junction aggregates are thought tightly regulated, though there is evidence that so-called connexon hemichannels may open in certain pathological conditions. It is presently not known whether undocked connexons are concentrated in specialized domains of membrane. Recently, we reported that interaction between the MAGUK scaffolding protein Zonula Occludens-1 (ZO-1) and the gap junction protein connexin 43 (Cx43) is concentrated in a region of the plasma membrane surrounding the gap junction plaque called the perinexus. It was found that ZO-1-Cx43 interaction governs a balance between undocked connexons in the perinexus and connexons docked in functional intercellular channels in the gap junction. In ongoing work it has been determined that the perinexus of cardiomyocyte gap junctions likely does contain high concentrations of undocked connexons composed of Cx43. This connexon-enriched zone of membrane appears to be a specialized nidus for integration of channel, junctional, and signal transduction molecules. Further insight into the function of the perinexus could provide new therapeutic avenues for the treatment of arrhythmia and other cardiac diseases.