Coupling of Slack and NaV1.6 sensitizes Slack to quinidine blockade and guides anti-seizure strategy development

Author:

Yuan Tian1,Wang Yifan1,Jin Yuchen1,Yang Hui1,Xu Shuai1,Zhang Heng2,Chen Qian1,Li Na1,Ma Xinyue1,Song Huifang1,Peng Chao1,Geng Ze1,Dong Jie1,Duan Guifang1,Sun Qi1,Yang Yang3ORCID,Yang Fan42,Huang Zhuo15ORCID

Affiliation:

1. State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center

2. NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University

3. Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University

4. Department of Biophysics, Kidney Disease Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou

5. IDG/McGovern Institute for Brain Research, Peking University

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 Na V 1.6 and Slack. Na V 1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of Na V 1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. Na V 1.6-mediated sensitization requires the involvement of Na V 1.6’s N-and C-termini binding to Slack’s C-terminus, and is enhanced by transient sodium influx through Na V 1.6. Moreover, disrupting the Slack-Na V 1.6 interaction by viral expression of Slack’s C-terminus can protect against SlackG269S-induced seizures in mice. These insights about a Slack-Na V 1.6 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.

Publisher

eLife Sciences Publications, Ltd

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