Coupling of Slack and Na<sub>V</sub>1.6 sensitizes Slack to quinidine blockade and guides anti-seizure strategy development.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38289338.
- Also identified by DOI 10.7554/eLife.87559 and PMC identifier 10942592.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sub>V</sub>1.6 and Slack. Na<sub>V</sub>1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of Na<sub>V</sub>1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. Na<sub>V</sub>1.6-mediated sensitization requires the involvement of Na<sub>V</sub>1.6's N- and C-termini binding to Slack's C-terminus and is enhanced by transient sodium influx through Na<sub>V</sub>1.6. Moreover, disrupting the Slack-Na<sub>V</sub>1.6 interaction by viral expression of Slack's C-terminus can protect against Slack<sup>G269S</sup>-induced seizures in mice. These insights about a Slack-Na<sub>V</sub>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.
Medical subject headings
- Epilepsy
- NAV1.6 Voltage-Gated Sodium Channel
- Quinidine