Cardiac sodium channel complexes and arrhythmia: structural and functional roles of the β1 and β3 subunits

In cardiac myocytes, the voltage-gated sodium channel Na_V 1.5 opens in response to membrane depolarisation and initiates the action potential. The Na_V 1.5 channel is typically associated with regulatory β-subunits that modify gating and trafficking behaviour. These β-subunits contain a single extracellular immunoglobulin (Ig) domain, a single transmembrane α-helix and an intracellular region. Here we focus on the role of the β1 and β3 subunits in regulating Na_V 1.5. We catalogue β1 and β3 domain specific mutations that have been associated with inherited cardiac arrhythmia, including Brugada syndrome, long QT syndrome, atrial fibrillation and sudden death. We discuss how new structural insights into these proteins raises new questions about physiological function.