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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.

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