Potassium sodium-activated channel subfamily T member 1 (KCNT1) isoform B F313L mutant (KCNT1 (F313L))

The KCNT1B channel (isoform B of KCNT1) is a sodium-activated potassium channel, also known as Slack or KNa1.1, which is predominantly expressed in the mammalian central nervous system [1, 12]. It plays a critical role in regulating neuronal excitability by mediating the slow afterhyperpolarization (AHP) that follows repetitive action potential firing, thereby preventing hyperexcitability [1, 5]. The F313L mutation in the KCNT1B isoform is a gain-of-function variant that leads to pathologically increased potassium currents [3, 4]. This excessive channel activity is a primary driver of severe, drug-resistant early-onset epileptic encephalopathies, including epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant sleep-related hypermotor epilepsy (ADSHE) [5, 10]. Pharmacological targeting of this mutant involves the use of channel blockers such as quinidine, and more recently, research has highlighted hydroquinine and tipepidine as potent inhibitors specific to this isoform and mutation [3, 4, 12]. Genetic therapies, including antisense oligonucleotides and siRNA (e.g., ATL-201), are also in development to reduce the expression of the mutant channel and restore normal electrical signaling in the brain [7].

Other names

Slack-BhKCNT1BSlo2.2KNa1.1KCa4.1Sequence Like A Calcium-activated K+ channelPotassium channel subfamily T member 1

Blockade or downregulation of the gain-of-function sodium-activated potassium channel to normalize neuronal excitability and suppress seizure activity