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

Voltage-gated sodium (Nav) channels drive the rising phase of the action potential, essential for electrical signalling in nerves and muscles. The Nav channel alpha-subunit contains the ion-selective pore. In the cardiomyocyte, Nav1.5 is the main Nav channel alpha-subunit isoform, with a smaller expression of neuronal Nav channels. Four distinct regulatory beta-subunits (beta 1-4) bind to the Nav channel alpha-subunits. Previous work has emphasised the beta-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 beta-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 beta-subunits interact with Nav1.5 in a different way from their binding to other Nav channel isoforms. We believe this feature may facilitatetrans-cell-adhesion between beta 1-associated Nav1.5 subunits on the intercalated disc and promote ephaptic conduction between cardiomyocytes.