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- Title
Coupling of Slack and NaV1.6 sensitizes Slack to quinidine blockade and guides anti-seizure strategy development.
- Authors
Tian Yuan; Yifan Wang; Yuchen Jin; Hui Yang; Shuai Xu; Heng Zhang; Qian Chen; Na Li; Xinyue Ma; Huifang Song; Chao Peng; Ze Geng; Jie Dong; Guifang Duan; Qi Sun; Yang Yang; Fan Yang; Zhuo Huang
- 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.
- Subjects
CONOTOXINS; QUINIDINE; DRUG discovery; BLOCKADE; SODIUM channels; ANTICONVULSANTS
- Publication
eLife, 2024, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.87559