Biophysics of Normal and Abnormal Cardiac Sodium Channel Function

Voltage-gated sodium channels (Na_v) underlie the activity of many excitable cells. In the heart, Na_v channels are responsible for the rapid cardiomyocyte action potential upstroke that promotes rapid conduction of the electrical impulse leading to coordinated mechanical contraction. Central to this function, Na_v channels activate (and then inactivate) rapidly in response to a small depolarization of the membrane, resulting in a large influx of Na⁺ ions and further membrane depolarization. Dysfunction in Na_v channel activity results in human diseases and disorders, including epilepsy, ataxia, cardiac arrhythmia, and myotonia.^1-3 Variants in SCN5A, the gene encoding the primary cardiac Na_v α-subunit Na_v1.5, have been linked to human arrhythmia syndromes including long QT type 3 (LQT3), Brugada syndrome, cardiac conduction disease, sinus node disease, and atrial fibrillation.^2,4,5 A detailed discussion of fundamental aspects of Na_v structure function, gating, and pharmacology can be found in Chapter 1. Here we discuss current understanding regarding regulation of Na_v biophysical activity and cellular function in health and disease.