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 β-subunits (β1–4) bind to the Nav channel α-subunits. Previous work has emphasised the β-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 β-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 β-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 β1-associated Nav1.5 subunits on the intercalated disc and promote ephaptic conduction between cardiomyocytes.
Highlights
Cardiomyocytes within cardiac muscle bundles perform the involuntary contraction and relaxation cycle that is the cellular basis of the heartbeat
Nav1.5 at the intercalated disc and on the sarcolemma may initiate the cardiac action potential as it propagates from one cardiomyocyte to another within the muscle fibre [5,6]
This, combined with the close structural association between the neuronal Nav1.5; sodium (Nav) channels, the sodium-calcium exchanger (NCX) and the voltage-gated calcium channels on the T-tubular membrane and with the ryanodine receptors (RyR) on the adjacent sarcoplasmic reticulum, permits T-tubular activation that is synchronous with the surface action potential and that optimally initiates excitation-contraction coupling [4,7]
Summary
Cardiomyocytes within cardiac muscle bundles perform the involuntary contraction and relaxation cycle that is the cellular basis of the heartbeat. The major Nav channel isoform expressed in the heart is Nav1.5 It is mainly localised at the intercalated disc and within caveolae on the sarcolemmal lateral membrane [3]. Cardiomyocytes express smaller amounts of the neuronal channels Nav1.1, Nav1.3 and Nav1.6, which are predominantly localised in the T-tubules [4,5] This pattern is striking and is likely to be functionally significant. This, combined with the close structural association between the neuronal Nav channels, the sodium-calcium exchanger (NCX) and the voltage-gated calcium channels on the T-tubular membrane and with the ryanodine receptors (RyR) on the adjacent sarcoplasmic reticulum, permits T-tubular activation that is synchronous with the surface action potential and that optimally initiates excitation-contraction coupling [4,7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
