Functional and pharmacological investigation on novel KCND3 variants identified in patients with early repolarization syndrome and refractory epilepsy

本研究的目的是阐明新的KCND3变异的电生理变化，并分析药物对变异的药理作用。这些变异是难治性癫痫的原因，可能与早期复极综合征导致癫痫性心源性猝死（SUDEP）有关。我们成功建立了瞬时表达KCND3编码Kv4.3的培养细胞模型。变异的Ito通道引起了功能增益效应：Ito密度增加，激活和失活曲线向左移动，失活缓慢。此外，该变异从失活中恢复缓慢。因此，我们将一些候选药物应用于不同的通道，并确定了它们的前景。

The aim of this study is to elucidate the electrophysiological changes of novel KCND3 variants and to analyze the pharmacological effect of drugs to the variants. The variants are the cause of refractory epilepsy and might be related with early repolarization syndrome leading to sudden cardiac death in epilepsy (SUDEP).We have successfully created a cultured cell model with transiently expressing KCND3 encoding Kv4.3. The variant Ito channels caused gain-of-function effect: increase of Ito densities, leftward movement of activation and inactivation curves and slow inactivation. In addition, the variant showed slow recovery from inactivation. Therefore, we have applied some candidate drugs to variant channels and identified their promising effects.