Functional Na V 1.8 Channels in Intracardiac Neurons

Abstract

Rationale: The SCN10A gene encodes the neuronal sodium channel isoform Na V 1.8. Several recent genome-wide association studies have linked SCN10A to PR interval and QRS duration, strongly suggesting an as-yet unknown role for Na V 1.8 in cardiac electrophysiology. Objective: To demonstrate the functional presence of SCN10A /Nav1.8 in intracardiac neurons of the mouse heart. Methods and Results: Immunohistochemistry on mouse tissue sections showed intense Na V 1.8 labeling in dorsal root ganglia and intracardiac ganglia and only modest Na V 1.8 expression within the myocardium. Immunocytochemistry further revealed substantial Na V 1.8 staining in isolated neurons from murine intracardiac ganglia but no Na V 1.8 expression in isolated ventricular myocytes. Patch-clamp studies demonstrated that the Na V 1.8 blocker A-803467 (0.5–2 μmol/L) had no effect on either mean sodium current (I Na ) density or I Na gating kinetics in isolated myocytes but significantly reduced I Na density in intracardiac neurons. Furthermore, A-803467 accelerated the slow component of current decay and shifted voltage dependence of inactivation toward more negative voltages, as expected for blockade of Na V 1.8-based I Na . In line with these findings, A-803467 did not affect cardiomyocyte action potential upstroke velocity but markedly reduced action potential firing frequency in intracardiac neurons, confirming a functional role for Na V 1.8 in cardiac neural activity. Conclusions: Our findings demonstrate the functional presence of SCN10A /Na V 1.8 in intracardiac neurons, indicating a novel role for this neuronal sodium channel in regulation of cardiac electric activity.