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Article Dans Une Revue Frontiers in Physiology Année : 2018

KV4.3 Expression Modulates NaV1.5 Sodium Current

Vincent Portero
  • Fonction : Auteur
Ronald Wilders
  • Fonction : Auteur
Simona Casini
  • Fonction : Auteur
Arie O. Verkerk
  • Fonction : Auteur
Carol Ann Remme
  • Fonction : Auteur

Résumé

In cardiomyocytes, the voltage-gated transient outward potassium current (Ito) is responsible for the phase-1 repolarization of the action potential (AP). Gain-of-function mutations inKCND3, the gene encoding the Itocarrying KV4.3 channel, have been associated with Brugada syndrome (BrS). While the role of Itoin the pro-arrhythmic mechanism of BrS has been debated, recent studies have suggested that an increased Itomay directly affect cardiac conduction. However, the effects of an increased Itoon AP upstroke velocity or sodium current at the cellular level remain unknown. We here investigated the consequences of KV4.3 overexpression on NaV1.5 current and consequent sodium channel availability. We found that overexpression of KV4.3 protein in HEK293 cells stably expressing NaV1.5 (HEK293-NaV1.5 cells) significantly reduced NaV1.5 current density without affecting its kinetic properties. In addition, KV4.3 overexpression decreased AP upstroke velocity in HEK293-NaV1.5 cells, as measured with the alternating voltage/current clamp technique. These effects of KV4.3 could not be explained by alterations in total NaV1.5 protein expression. Using computer simulations employing a multicellularin silicomodel, we furthermore demonstrate that the experimentally observed increase in KV4.3 current and concurrent decrease in NaV1.5 current may result in a loss of conduction, underlining the potential functional relevance of our findings. This study gives the first proof of concept that KV4.3 directly impacts on NaV1.5 current. Future studies employing appropriate disease models should explore the potential electrophysiological implications in (patho)physiological conditions, including BrS associated withKCND3gain-of-function mutations.
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Dates et versions

hal-01833332 , version 1 (13-07-2018)

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Vincent Portero, Ronald Wilders, Simona Casini, Flavien Charpentier, Arie O. Verkerk, et al.. KV4.3 Expression Modulates NaV1.5 Sodium Current. Frontiers in Physiology, 2018, 9, pp.178. ⟨10.3389/fphys.2018.00178⟩. ⟨hal-01833332⟩
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