SCN10A-Dependent Late INa Current
Never Too Late for Cardiac Conduction?
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See Article by Macri et al
Voltage-gated Na+ channels are activated on depolarization leading to a rapid influx of Na+ ions (INa) generating the fast upstroke of the cardiac action potential (AP).1 Na+ channels usually inactivate within milliseconds after depolarization. However, some Na+ channels remain open (delayed inactivation or reopen), and a small but persistent influx of Na+ ions throughout the plateau of the AP occurs, generating a Na+ current referred to as Late INa. Although the amplitude of this Late INa is usually <1% of peak INa, this tiny current is still responsible for a substantial Na+ influx because it can persist for hundreds of milliseconds contributing to cardiac conduction/depolarization and function. From a pathophysiological standpoint, it is interesting that atrial fibrillation and heart failure are associated with enhanced Late INa.2,3 Besides modulation of the AP duration, enhanced Late INa leads to an increased myocellular Na+ entry, thereby increasing [Na+]I, this may be followed by subsequent Ca2+ overload because of the extrusion of Na+ ions via the reverse mode of the NCX (Na+/Ca2+ exchanger) and decreased Ca2+ extrusion through NCX during its forward mode. These mechanisms can give rise to early and delayed afterdepolarization thereby inducing arrhythmias and contractile dysfunction.
The cardiac Na+ channel Nav1.5 (encoded by the SCN5A gene) is known to be the main isoform in the human heart. However, other Nav isoforms exist, including the Nav1.8 channel (encoded by SCN10A, that is adjacent to SCN5A on chromosome 3), which is also known to be resistant to tetrodotoxin and was shown to influence cardiac conduction.4,5 Recently, …