The Cardiac Gap Junction has Discrete Functions in Electrotonic and Ephaptic Coupling

Abstract

Connexin43-formed gap junctions have long been thought to contribute to cardiac conduction in the mammalian ventricle by providing direct electrotonic connectivity between the cytoplasms of neighboring cardiomyocytes. However, accumulating data from studies of non-mammalian hearts, Connexin 43 (Cx43) knockout mice and human Cx43 mutations have raised questions as to whether gap junctions are the sole means by which electrical coupling between cardiomyocytes is accomplished. Computational and experimental work over the last decade have indicated that intercellular propagation of action potentials in the heart may involve both electrotonic and ephaptic contributions-in what has been dubbed "mixed-mode" conduction. Interestingly, the Cx43 gap junction may provide a common structural platform in mammals that facilitates the operation of these two mechanisms. In addition to gap junction channels functioning in an electrotonic role, the perinexus region at the edge of gap junctions may be provide a niche for voltage-gated sodium channels from neighboring cells to be in sufficiently close proximity to enable ephaptic transmission of action potential. A novel role has recently been identified in this potential ephaptic mechanism for inter-membrane adhesion mediated by the beta subunit (beta1/Scn1b) of the sodium channel. The new perspective of the operational redundancy that is built into cardiac electrical connectivity could provide new understanding of arrhythmia mechanisms and holds the promise for new approach to anti-arrhythmic therapy. Anat Rec, 302:93-100, 2019. © 2018 Wiley Periodicals, Inc.

Keywords: Nav1.5; Scn1b; beta subunit; cardiac gap junction Cx43 conduction Sodium Channel Ephaptic Scn5a.

Fig. 1.

The Gap Junction and Perinexus: In the top right intercalated disks are stained as red “bars” between ventricular cardiomyocytes. Below is a model of an intercalated disk between two cardiomyocytes, wherein the characteristic organization of the disk can be seen. Plicate (red corrugations), adhesion junction-rich, regions of the disk are separated by a step-like (blue) interplicate zone. Gap junctions are enriched in the interplicate zone and a model of the gap junction and adjacent perinexus is shown to the lower right. The gap junction comprises a cluster of intercellular gap junction channels, which dock within the narrow 2 nm “Gap” from which the structure derives its name. The membranes surrounding the gap junction form the perinexus and are enriched with undocked Cx43 hemichannels (Rhett et al., 2011; Rhett et al., 2012a; Veeraraghavan et al., 2015b; Veeraraghavan et al., 2018). A thin section electron micrograph of a gap junction and perinexus is shown in the top left.

Fig. 2.

The Gap Junction is Central to Both Electrotonic and Ephaptic Conduction: The cardiac gap junction is the structural basis of “mixed mode” conduction: The electrotonic mechanism being mediated by intercellular Cx43 gap junction channels and the ephaptic mechanism contributed to by clusters of sodium channels in the perinexal nano-domain within 100–200 nm of the gap junction edge.

Fig. 3.

Thin section electron micrograph of an intercalated disc in a cardiac-specific CKO mouse (from Gutstein et al., 2003). Intact adherens junctions (white arrowheads) and desmosomes (black arrowheads) are observed. While there are no gap junctions (and thus no perinexii) between ventricular myocytes in the CKO mutant mouse, intercalated disk regions of extremely close contact between cells are still observed (inset). Asterisks indicate a number of locations with membrane-membrane contacts of <30 nm, i.e., below the “Mori limit.” Bar = 140 nm.