Coupling of Slack and Na_V1.6 sensitizes Slack to quinidine blockade and guides anti-seizure strategy development.

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_V1.6 and Slack. Na_V1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of Na_V1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. Na_V1.6-mediated sensitization requires the involvement of Na_V1.6's N- and C-termini binding to Slack's C-terminus and is enhanced by transient sodium influx through Na_V1.6. Moreover

SUBMITTER: Yuan T 

PROVIDER: S-EPMC10942592 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature