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Lack of modulatory effect of the SCN5A R1193Q polymorphism on cardiac fast Na(+) current at body temperature

SCN5A encodes the main subunit of the Na(V)1.5 channel, which mediates the fast Na(+) current responsible for generating cardiac action potentials. The single nucleotide polymorphism SCN5A(R1193Q), which results in an amino acid replacement in the subunit, is common in East Asia. SCN5A(R1193Q) is of...

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Detalles Bibliográficos
Autores principales: Abe, Masayoshi, Kinoshita, Koshi, Matsuoka, Kenta, Nakada, Takahito, Miura, Kimiaki, Hata, Yukiko, Nishida, Naoki, Tabata, Toshihide
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231685/
https://www.ncbi.nlm.nih.gov/pubmed/30419068
http://dx.doi.org/10.1371/journal.pone.0207437
Descripción
Sumario:SCN5A encodes the main subunit of the Na(V)1.5 channel, which mediates the fast Na(+) current responsible for generating cardiac action potentials. The single nucleotide polymorphism SCN5A(R1193Q), which results in an amino acid replacement in the subunit, is common in East Asia. SCN5A(R1193Q) is often identified in patients with type 3 long QT syndrome and Brugada syndrome. However, its linkage to arrhythmic disorders is under debate. Previous electrophysiological studies performed at room temperature inconsistently reported the gain- or loss-of-function effect of SCN5A(R1193Q) on the Na(V)1.5 channel. More recently, it was theoretically predicted that SCN5A(R1193Q) would exert a loss-of-function effect at body temperature. Here, we experimentally assessed whether SCN5A(R1193Q) modulates the Na(V)1.5 channel at various temperatures including normal and febrile body temperatures. We compared voltage-gated Na(+) currents in SCN5A(R1193Q)-transfected and wild-type SCN5A-transfected HEK293T cells using a whole-cell voltage-clamp technique. First, we made comparisons at constant temperatures of 25°C, 36.5°C, and 38°C, and found no difference in the conductance density, voltage dependence of gating, or time dependence of gating. This suggested that SCN5A(R1193Q) does not modulate the Na(V)1.5 channel regardless of temperature. Second, we made comparisons while varying the temperature from 38°C to 26°C in 3 min, and again observed no difference in the time course of the amplitude or time dependence of gating during the temperature change. This also indicated that SCN5A(R1193Q) does not modulate the Na(V)1.5 channel in response to an acute body temperature change. Therefore, SCN5A(R1193Q) may not be a monogenic factor that triggers arrhythmic disorders.