The perinexus: sign-post on the path to a new model of cardiac conduction?

Abstract

The perinexus is a recently identified microdomain surrounding the cardiac gap junction that contains elevated levels of connexin43 and the sodium channel protein, Nav1.5. Ongoing work has established a role for the perinexus in regulating gap junction aggregation. However, recent studies have raised the possibility of a perinexal contribution at the gap junction cleft to intercellular propagation of action potential via non-electrotonic mechanisms. The latter possibility could modify the current theoretical understanding of cardiac conduction, help explain paradoxical experimental findings, and open up entirely new avenues for antiarrhythmic therapy. We review recent structural insights into the perinexus and its potential novel functional role in cardiac-excitation spread, highlighting presently unanswered questions, the evidence for ephaptic conduction in the heart and how structural insights may help complete this picture.

Figure 1. The perinexus

A) Freeze fracture electron micrograph showing en face view of a gap junction plaque in ventricular myocardium (outlined by dashed black line) surrounded by perinexus (tinted orange) at 98000x magnification (Severs, 2002). Individual connexons, seen as particles, are densely packed in a hexagonal array within the gap junction (solid rectangle) but are less concentrated and organized within the perinexus (dashed rectangle). B) Transmission electron micrograph of gap junction in ventricular myocardium flanked on either side by perinexus. Space between perinexal membranes is tinted orange. A desmosome is also visible on the right hand side. C) Duolink labeling shows Cx43/Na_v1.5 interaction at and surrounding GJs in neonatal rat ventricular myocytes. Cx43 is labeled in green, Cx43/Nav1.5 interaction is labeled by Duolink in red, and the nucleus is blue.

Figure 2. Structural organization of channels within the perinexus

The transmission electron micrograph from figure 1B is repeated with the gap junction highlighted in green, the perinexus in orange and the desmosome in blue. The schematic cartoon above shows the regular organization of connexons within the gap junction and the localization of Cx43 hemichannels and Na_v1.5 channels to the perinexus. Arrowheads point to the confined extracellular cleft between apposed cell membranes within the gap junction and the perinexus. While the cartoon shows a simplified view of the perinexus, the reader should remember that the structural organization of the channel proteins shown here is governed by their interactions with multiple structural proteins such as ZO-1, SAP97, that are not shown (Rhett and Gourdie, 2012). Furthermore, these structures are far from static, with connexons constantly flowing into the gap junction at its periphery.