The role of the gap junction perinexus in cardiac conduction: Potential as a novel anti-arrhythmic drug target

Abstract

Cardiovascular disease remains the single largest cause of natural death in the United States, with a significant cause of mortality associated with cardiac arrhythmias. Presently, options for treating and preventing myocardial electrical dysfunction, including sudden cardiac death, are limited. Recent studies have indicated that conduction of electrical activation in the heart may have an ephaptic component, wherein intercellular coupling occurs via electrochemical signaling across narrow extracellular clefts between cardiomyocytes. The perinexus is a 100-200 nm-wide stretch of closely apposed membrane directly adjacent to connexin 43 gap junctions. Electron and super-resolution microscopy studies, as well as biochemical analyses, have provided evidence that perinexal nanodomains may be candidate structures for facilitating ephaptic coupling. This work has included characterization of the perinexus as a region of close inter-membrane contact between cardiomyocytes (<30 nm) containing dense clusters of voltage-gated sodium channels. Here, we review what is known about perinexal structure and function and the potential that the perinexus may have novel and pivotal roles in disorders of cardiac conduction. Of particular interest is the prospect that cell adhesion mediated by the cardiac sodium channel β subunit (Scn1b) may be a novel anti-arrhythmic target.

Keywords: Arrhythmia; Conduction; Ephaptic; Gap junctions; Heart; Na(V)1.5/Scn5a; Perinexus; β1/Scn1b.

Figure 1:

Representative molecules from the four primary classes of existing anti-arrhythmic drugs (AADs).

Figure 2:

Schematic model illustrating the gap junction and perinexus. Top over view of two myocytes interacting act an intercalated disk. Note that gap junctions are prominently found in the interplicate regions of the disk. Middle of gap junction and surrounding perinexus. Note the depiction of clusters of the trans-interacting sodium channel complexes in the perinexus. The electron micrograph of a gap junction and its adjacent peri-junctional regions now dubbed the perinexus is reproduced from Dewey and Barr, 1965. The cleft of extracellular space bounded by perinexal membranes is indicated by blue highlights.

Figure 3:

Schematic of the spacing afforded by trans-adhesion of two β1 subunits (green) on apposed membranes at the GJ perinexus. The distance of two trans-interacting β1 subunits would maintain an inter-membrane spacing within the limit specified by Mori and co-workers (2008) for the theoretical cardiac ephapse.