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 ; 2  ; 3 Variants in SCN5A , the gene encoding the primary cardiac Na v α-subunit Na v 1.5, 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.