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 mol/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. Key Words: sodium channels Ⅲ autonomic nervous system Ⅲ cardiac electrophysiology Ⅲ SCN10A V oltage-gated sodium (Na V ) channels play a critical role in the rising phase of the action potential and are essential for impulse generation and conduction in most excitable cells. They are composed of 1 large pore-forming ␣-subunit and 1 or more ancillary ␤-subunits. 1 Several ␣-subunit sodium channel isoforms have been identified that display different physiological and pharmacological properties and distinct expression patterns in the nervous system, skeletal muscle, or cardiomyocytes. 2 In the myocardium, Na V 1.5 (encoded by the SCN5A gene) is the most prominent sodium channel determining cardiac conduction, but other sodium channel isoforms may also be present in the heart. 3 In neural tissue, the sodium channel isoform Na V 1.8 (encoded by the SCN10A gene) is highly expressed in small-and medium-diameter nociceptive sensory neurons of the dorsal root ganglia (DRG) and cranial sensory ganglia. 4,5 Na V 1.8 function has mostly been associated with pain perception, 6,7 but several recent genome-wide association studies have also linked SCN10A to PR interval and QRS duration on the ECG. 8 -11 Furthermore, the SCN10A locus was also found to be associated with atrial fibrillation. 10 These observations strongly suggest a role for Na V 1.8 in cardiac electrophysiology, but its function in the heart remains to be elucidated. Conclusions:

Neuronal Na v 1.8 Channels as a Novel Therapeutic Target of Acute Atrial Fibrillation Prevention

“…Gating properties were also changed under A‐803467 with hyperpolarized steady‐state inactivation and delayed recovery from inactivation. Interestingly, the left‐shifted steady‐state inactivation was quite consistent with the effect of A‐803467 in isolated mouse intracardiac neurons delineated by Verkerk et al 36. Like other sodium channel blockers, our results support that A‐803467 might block sodium channels in an inactivated state and the number of trapped inactivated sodium channels might be increased during repeated stimulation.…”

“…There is an increased number of studies that focus on the relationship of SCN10A /Na v 1.8 with cardiac diseases. In spite of several disputes such as the expression of Na v 1.8 in the heart,36, 39 Na v 1.8 is critical in cardiac electrophysiology. Our previous study first reported 17 putative pathogenic SCN10A variants in 25 of 150 Brugada syndrome probands with a positive proband yield of 16.7%, approaching our historical yield of 20.1% for SCN5A .…”

Cardiac ion channels

“…16 In cardiac myocytes, block of Nav1.8 reduces late Na C current and shortens action potential duration, 17 while block of Nav1.8 in intracardiac neurons reduces action potential frequency. 18 How these observations relate to cardiac conduction is not entirely clear. 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.…”

Association Between Genetic Variation in the <i>SCN10A</i> Gene and Cardiac Conduction Abnormalities in Patients With Hypertrophic Cardiomyopathy

“…27) It is characterized by a long-duration action potential and preservation of excitability during rapid and sustained stimulation. SC-N10A has been recently identified in the human heart [28][29][30] and has been associated in GWAS with alterations in cardiac conduction, especially atrioventricular conduction (PR interval).…”