Cell-Adhesion Properties of ß-Subunits in the Regulation of Cardiomyocyte Sodium Channels.

ABSTRACT

Voltage-gated sodium (Nav) channels drive the rising phase of the action potential, essential for electrical signalling in nerves and muscles. The Nav channel α-subunit contains the ion-selective pore. In the cardiomyocyte, Nav1.5 is the main Nav channel α-subunit isoform, with a smaller expression of neuronal Nav channels. Four distinct regulatory ß-subunits (ß1-4) bind to the Nav channel α-subunits. Previous work has emphasised the ß-subunits as direct Nav channel gating modulators. However, there is now increasing appreciation of additional roles played by these subunits. In this review, we focus on ß-subunits as homophilic and heterophilic cell-adhesion molecules and the implications for cardiomyocyte function. Based on recent cryogenic electron microscopy (cryo-EM) data, we suggest that the ß-subunits interact with Nav1.5 in a different way from their binding to other Nav channel isoforms. We believe this feature may facilitate trans-cell-adhesion between ß1-associated Nav1.5 subunits on the intercalated disc and promote ephaptic conduction between cardiomyocytes.