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

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.