PDF(Pubmed)
Abstract：
Quinidine has been used as an anticonvulsant to treat patients with KCNT1-related epilepsy by targeting gain-of-function KCNT1 pathogenic mutant variants. However, the detailed mechanism underlying quinidine\'s blockade against KCNT1 (Slack) remains elusive. Here, we report a functional and physical coupling of the voltage-gated sodium channel NaV1.6 and Slack. NaV1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of NaV1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. NaV1.6-mediated sensitization requires the involvement of NaV1.6\'s N- and C-termini binding to Slack\'s C-terminus and is enhanced by transient sodium influx through NaV1.6. Moreover, disrupting the Slack-NaV1.6 interaction by viral expression of Slack\'s C-terminus can protect against SlackG269S-induced seizures in mice. These insights about a Slack-NaV1.6 complex challenge the traditional view of \'Slack as an isolated target\' for anti-epileptic drug discovery efforts and can guide the development of innovative therapeutic strategies for KCNT1-related epilepsy.
摘要：
奎尼丁已被用作抗惊厥药，通过靶向功能获得KCNT1致病性突变变体来治疗KCNT1相关癫痫患者。然而,奎尼丁阻断KCNT1（Slack）的详细机制仍然难以捉摸。这里,我们报道了电压门控钠通道NaV1.6和Slack的功能和物理耦合。NaV1.6结合并高度敏感Slack对奎尼丁阻断。NaV1.6的纯合敲除降低了天然钠激活的钾电流对奎尼丁阻断的敏感性。NaV1.6介导的致敏需要NaV1.6的N-和C-末端与Slack的C-末端结合的参与，并且通过NaV1.6的瞬时钠流入增强。此外，通过Slack的C端病毒表达破坏Slack-NaV1.6相互作用可以防止SlackG269S诱导的小鼠癫痫发作。这些关于Slack-NaV1.6复合物的见解挑战了传统的观点，即“Slack作为抗癫痫药物发现工作的孤立目标”，并可以指导KCNT1相关癫痫的创新治疗策略的开发。
