Heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms

The cardiac sodium channel Na_V1.5, encoded by the SCN5A gene, is responsible for the fast upstroke of the action potential. Mutations in SCN5A may cause sodium channel dysfunction by decreasing peak sodium current, which slows conduction and facilitates reentry-based arrhythmias, and by enhancing late sodium current, which prolongs the action potential and sets the stage for early afterdepolarization and arrhythmias. Yet, some Na_V1.5-related disorders, in particular structural abnormalities, cannot be directly or solely explained on the basis of defective Na_V1.5 expression or biophysics. An emerging concept that may explain the large disease spectrum associated with SCN5A mutations centres around the multifunctionality of the Na_V1.5 complex. In this alternative view, alterations in Na_V1.5 affect processes that are independent of its canonical ion-conducting role. We here propose a novel classification of Na_V1.5 (dys)function, categorized into (i) direct ionic effects of sodium influx through Na_V1.5 on membrane potential and consequent action potential generation, (ii) indirect ionic effects of sodium influx on intracellular homeostasis and signalling, and (iii) non-ionic effects of Na_V1.5, independent of sodium influx, through interactions with macromolecular complexes within the different microdomains of the cardiomyocyte. These indirect ionic and non-ionic processes may, acting alone or in concert, contribute significantly to arrhythmogenesis. Hence, further exploration of these multifunctional effects of Na_V1.5 is essential for the development of novel preventive and therapeutic strategies.