Whither Art Thou, SCN10A, and What Art Thou Doing?

Abstract

Since its initial cloning in 1992, SCN5A (Nav1.5) has become known as "the" cardiac sodium channel. 1 SCN5A encodes a tetrodotoxin (TTX)-resistant channel that is responsible for the inward sodium current (I Na ), which initiates the cardiac action potential. Its RNA and protein expression dominate the sodium channel landscape in the ventricle, atrium, and specialized conduction system. Mice heterozygous for a targeted Scn5a deletion (Scn5a ϩ/Ϫ mice) have slowed conduction along with atrial and ventricular arrhythmias, whereas homozygous targeted deletion in mice is embryonic lethal. 2 In humans, pharmacological agents that block SCN5A such as flecainide, developed as antiarrhythmics, are proarrhythmic and increase mortality in patients with structural heart disease. 3 In addition, SCN5A mutations cause a potpourri of diseases that lead to sudden cardiac death including long-QT syndrome type 3 (LQT3, gain-of-function mutations that slow inactivation and increase late sodium current, I Na,L ), Brugada syndrome (BRS1, loss of function mutations that decrease peak I Na ), conduction disease, atrial fibrillation, and dilated cardiomyopathy. 4 More recently, changes in SCN5A (expression, splicing, posttranslational modifications including CaMKII phosphorylation) and/or its ␤-subunits that decrease peak I Na or increase I Na,L have been implicated as potential contributing factors for more common types of sudden death from acquired heart diseases such as heart failure. 5-8 Articles, see p 322 and 333A number of independent lines of evidence have suggested that other sodium channels might play important roles in the heart. In the mouse, Scn5a is preferentially localized at intercalated disks, whereas Nav1.1, Nav1.3, and Nav1.6 are localized in t-tubules. 9 Consistent with this, TTX-sensitive sodium channels were shown to be responsible for 16% of the sodium channel mRNA and 8% of the peak I Na in isolated adult cardiac myocytes and were upregulated in cardiac myocytes isolated from rats with thoracic aortic bandinginduced heart failure and increased I Na,L . 10,11 SCN10A (Nav1.8) is another TTX-resistant sodium channel located adjacent to SCN5A on human chromosome 3p21-22 that was originally identified in neurons. 12,13 Scn10a mRNA is also expressed in both in isolated mouse atrial and ventricular myocytes, and Scn10a Ϫ/Ϫ mice have shorter PR intervals during ambulatory telemetry monitoring than wild-type littermates. In contrast, other investigators have shown that wild-type mice treated acutely with the Scn10a-specific blocker A-803467 have longer PR and wider QRS intervals during both ambulatory telemetry monitoring and invasive electrophysiology studies. 14 Thus, the molecular evidence favors a role for other sodium channels in general and Scn10a in particular in the rodent heart. SCN10A mRNA is also expressed in human heart tissue. 13 Unexpectedly, evidence for a role for SCN10A in human cardiac electrophysiology came from genome-wide association studies (GWAS). Using PR and/or QRS intervals as intermediate phenot...

A common genetic variant within SCN10A modulates cardiac SCN5A expression

“…The mouse homozygous null phenotype is embryonic lethal, and mice haploinsufficient for Scn5a display a host of profound cardiac rhythm disturbances, including slowed cardiac conduction and a Brugada-like phenotype, similar to those associated with SNPs at neighboring SCN10A (2,5). In contrast, whether the SCN10A product Na v 1.8 plays a role in cardiac physiology remains controversial (11)(12)(13). The Scn10a knockout mouse displayed subtle cardiac ECG abnormalities, including modest PR interval shortening indicative of more rapid than normal conduction (2).…”

“…However, functional follow-up analysis of SCN10A provided conflicting evidence about whether Na v 1.8 accelerates (5) or slows (2) conduction velocity, and the magnitude of the effects of blocking Scn10a in mice was small (2,5). Therefore, the role of SCN10A in cardiac physiology remained controversial (11)(12)(13).…”

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

“…Furthermore, the Na V 1.8 channel protein encoded by SCN10A was reported to be expressed in working myocardium and the cardiac conduction system (475). Others, however, have found its expression restricted to intracardiac neurons (436), and the impact of Na V 1.8 on the cardiac sodium current is debated (256). Whereas Na V 1.5 is the main depolarizing current in atria, conduction system, and ventricle, it is absent in the core of the nodes where Ca V currents are suggested to serve this function, albeit with slower kinetics (271,305,323).…”

Cardiac ion channels

“…The picture is further complicated by the findings that SCN10A knock-out mice display a decreased PR interval, while pharmacological inhibition of Nav1.8 causes PR prolongation. 19 The human polymorphisms occur in non-coding regions of SCN10A and their functional consequences are not known. Recent data suggest that at least one of these polymorphisms may affect transcriptional regulation of SCN5A and/or SCN10A.…”