Functional Nav1.8 channels in intracardiac neurons: the link between SCN10A and cardiac electrophysiology.
BACKGROUND
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.


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.
Department of Anatomy, Embryology, and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Arie O
AO
Verkerk
Carol Ann
CA
Remme
Cees A
CA
Schumacher
Brendon P
BP
Scicluna
Rianne
R
Wolswinkel
Berend
B
de Jonge
Connie R
CR
Bezzina
Marieke W
MW
Veldkamp
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D004594:Electrophysiology / Q000379:methods*; D005260:Female; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000502:physiology*; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009475:Neurons, Afferent / Q000378:metabolism / Q000502:physiology*; D015222:Sodium Channels / Q000502:physiology*
D062559:NAV1.8 Voltage-Gated Sodium Channel; C568318:Scn10a protein, mouse; D015222:Sodium Channels