Kcnt2, also known as Slick, encodes for pore-forming alpha subunits of the sodium-activated potassium (KNa) channel. This channel is rapidly gating, weakly voltage-dependent and sodium-dependent, and is involved in regulating neuronal excitability. It is expressed in specific neurons like those in the dorsal root ganglia, playing a role in pain-related processes [2].

In Slick knockout (KO) mice, increased basal heat detection and exacerbated thermal hyperalgesia were observed during neuropathic and chronic inflammatory pain. Electrophysiologic recordings of dorsal root ganglia neurons from these KO mice showed that Slick channels contribute to outward current, action potential firing propensity, and action potential properties, suggesting that Kcnt2-encoded channels restrain the excitability of certain neurons to diminish pain behavior [2].

Pathogenic variants in Kcnt2 are rare causes of developmental epileptic encephalopathy (DEE). Studies on patients with Kcnt2-related DEE found various phenotypes such as intellectual disability/developmental delay, epilepsy, neurological impairment, and dysmorphisms. In vitro functional studies of Kcnt2 variants showed gain-of-function (GoF) or loss-of-function (LoF) features, and different drugs had specific effects on these variants, indicating the need for in-vitro functional and pharmacological investigation for targeted therapies [1].

In conclusion, Kcnt2 plays a crucial role in regulating neuronal excitability, with implications for pain perception and epilepsy. The study of Kcnt2 using KO mouse models has provided insights into its function in pain-related biological processes, and research on human Kcnt2-related disorders has revealed its significance in developmental epileptic encephalopathies, highlighting potential directions for therapeutic development.