Localisation of SCN10A Gene Product Nav1.8 and Novel Pain-Related Ion Channels in Human Heart

Abstract

SummaryWe have shown that the gene SCN10A encoding the sodium channel Na v 1.8 is a susceptibility factor for heart block and serious ventricular arrhythmia. Since Na v 1.8 is known to be present in nerve fibres that mediate pain, it may be related to both cardiac pain and dysrhythmia. The localisation of Na v 1.8 and other key nociceptive ion channels, including Na v 1.7, Na v 1.9, capsaicin receptor TRPV1, and purinergic receptor P2X 3 , have not been reported in human heart. The aim of this study was to determine the distribution of Na v 1.8, related sodium and other sensory channels in human cardiac tissue, and correlate their density with sympathetic nerves, regenerating nerves (GAP-43), and vascularity. Human heart atrial appendage tissues (n = 13) were collected during surgery for valve disease. Tissues were investigated by immunohistology using specific antibodies to Na v 1.8 and other markers. Na v 1.8 immunoreactivity was detected in nerve fibres and fascicles in the myocardium, often closely associated with small capillaries. Na v 1.8 nerve fibres per mm 2 correlated significantly with vascular markers. Na v 1.8-immunoreactivity was present also in cardiomyocytes with a similar distribution pattern to that seen with connexins, the specialised gap junction proteins of myocardial intercalated discs. Na v 1.5-immunoreactivity was detected in cardiomyocytes but not in nerve fibres. Na v 1.7, Na v 1.9, TRPV1, P2X 3 /P2X 2 , and GAP43 positive nerve fibres were relatively sparse, whereas sympathetic innervation and connexin43 were abundant. We conclude that sodium channel Na v 1.8 is present in sensory nerves and cardiomyocytes of human heart. Na v 1.8 and other pain channels provide new targets for the understanding and treatment of cardiac pain and dysrhythmia. (Int Heart J 2011; 52: 146-152)

Functional Na V 1.8 Channels in Intracardiac Neurons

“…25 Recently, Facer et al also demonstrated the presence of Na V 1.8-immunoreactive sensory nerve fibers in human atrial myocardium. 26 The results from our study now provide the first evidence for a functional role for Na V 1.8 in regulation of cardiac neural activity. Using a specific blocker of Na V 1.8, 27 we confirmed the functional presence of Na V 1.8-based channels in intracardiac neurons and its role in regulating neuronal action potential firing frequency.…”

Novel <i>SCN3B</i> Mutation Associated With Brugada Syndrome Affects Intracellular Trafficking and Function of Nav1.5

“…34 A pore-forming subunit of the voltage-gated sodium channel in the sensory nervous and atrial myocardium, Nav1.8, is highly homologous to Nav1.5. 35 It was reported that an endoplasmic reticulum (ER) retention sequence, RRR, in the cytoplasmic loop I of Nav1.8 caused retention of Nav1.8 on the ER, and masking of the retaining signal by Navβ3 released Nav1.8 for trafficking to the cell surface. 36 Because the RRR sequence is conserved in the cytoplasmic loop I of Nav1.5, Navβ3 might alter Nav1.5 trafficking by masking its ER retensurface, whereas both Navβ3-L10P and Navβ3-V110I were retained in the cytoplasm (Figures 2B-a-f).…”

Cardiac ion channels

“…14,15 Subsequently, Nav1.8 expression was demonstrated in mouse and human cardiac myocytes and intracardiac neurons. 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.…”