Absence of Functional Nav1.8 Channels in Non-diseased Atrial and Ventricular Cardiomyocytes

Simona Casini,Fransisca A Nariswari,Arie O Verkerk,Kaomei Guan,Nicoline W.E Van Den Berg,Joris R De Groot,Vincent Portero,Gerard A Marchal,Isabella Mengarelli,Antoine H.G Driessen,Makiri Kawasaki,Carol Ann Remme,Marieke W Veldkamp

doi:10.1007/s10557-019-06925-6

Abstract

PurposeSeveral studies have indicated a potential role for SCN10A/NaV1.8 in modulating cardiac electrophysiology and arrhythmia susceptibility. However, by which mechanism SCN10A/NaV1.8 impacts on cardiac electrical function is still a matter of debate. To address this, we here investigated the functional relevance of NaV1.8 in atrial and ventricular cardiomyocytes (CMs), focusing on the contribution of NaV1.8 to the peak and late sodium current (INa) under normal conditions in different species.MethodsThe effects of the NaV1.8 blocker A-803467 were investigated through patch-clamp analysis in freshly isolated rabbit left ventricular CMs, human left atrial CMs and human-induced pluripotent stem cell-derived CMs (hiPSC-CMs).ResultsA-803467 treatment caused a slight shortening of the action potential duration (APD) in rabbit CMs and hiPSC-CMs, while it had no effect on APD in human atrial cells. Resting membrane potential, action potential (AP) amplitude, and AP upstroke velocity were unaffected by A-803467 application. Similarly, INa density was unchanged after exposure to A-803467 and NaV1.8-based late INa was undetectable in all cell types analysed. Finally, low to absent expression levels of SCN10A were observed in human atrial tissue, rabbit ventricular tissue and hiPSC-CMs.ConclusionWe here demonstrate the absence of functional NaV1.8 channels in non-diseased atrial and ventricular CMs. Hence, the association of SCN10A variants with cardiac electrophysiology observed in, e.g. genome wide association studies, is likely the result of indirect effects on SCN5A expression and/or NaV1.8 activity in cell types other than CMs.

Highlights

IntroductionAn exception is NaV1.8, encoded by the SCN10A gene
Sodium channels play a central role in the initiation and propagation of the action potential (AP) in excitable cells, Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Cardiovasc Drugs Ther (2019) 33:649–660 by micromolar concentrations of tetrodotoxin (TTX) [i.e. TTX-resistant], most neuronal isoforms are more TTXsensitive and inhibited by nanomolar concentrations [4]
We here investigated the functional relevance of NaV1.8 in atrial and ventricular cardiomyocytes, focusing on the contribution of NaV1.8 to the peak and late inward sodium current (INa) under normal conditions in different species

Summary

Introduction

An exception is NaV1.8, encoded by the SCN10A gene This isoform is mainly expressed in dorsal root ganglia, plays a role in pain perception [5] and is inhibited only by micromolar TTX concentrations, similar to NaV1.5 [4]. We and others have shown that NaV1.8 is expressed in murine, canine and human cardiac neurons [18, 20, 21], suggesting a function of the SCN10A gene product for cardiac conduction via modulation of AP firing in intracardiac neurons [18, 21, 22]. Electrophysiological studies in non-diseased human cardiomyocytes aimed at defining the physiological role of NaV1.8 in the human heart are limited To address these issues, we here investigated the functional relevance of NaV1.8 in atrial and ventricular cardiomyocytes, focusing on the contribution of NaV1.8 to the peak and late INa under normal conditions in different species

Methods

Results

Conclusion