Key result
NaV1.6 co-expression sensitizes Slack to quinidine ~100-fold, and disrupting this interaction protects against murine seizures.
Why the study?
Quinidine treats KCNT1-related epilepsy by targeting gain-of-function variants, but the detailed mechanism underlying its blockade against Slack remains elusive.
Absolute Event Rate: 0.87% vs 85.13%
NaV1.6 physically and functionally couples with Slack, sensitizing it to quinidine blockade, which provides a novel therapeutic target mechanism for KCNT1-related epilepsy.
Offers a potential target in KCNT1 epilepsy; leaves open translation from mouse models to patients.
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.
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Tian et al. (2023) studied KCNT1-related epilepsy. NaV1.6 co-expression vs. Slack expressed alone was evaluated on IC50 for quinidine blockade. Co-expression of NaV1.6 sensitized Slack to quinidine blockade by nearly 100-fold (IC50 0.87 μM vs 85.13 μM), and disrupting this interaction protected against SlackG269S-induced seizures in mice.
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