Targeting KNa1.1 channels in KCNT1-associated epilepsy

GOF pathogenic variants of KCNT1 underlie a broad spectrum of severe and refractory developmental and epileptic encephalopathies accompanied by intellectual disabilities. KCNT1 variants likely cause hyperexcitability by impairing GABAergic neuron excitability. Inhibition of mutant KNa1.1 channels is the current strategy to suppress hyperexcitability. Known inhibitors block the inner-pore vestibule of KNa1.1, similarly to how they inhibit cardiac hERG channels. Potent inhibition of hERG is one of the limiting factors for their use, as well as low potency. Potent small-molecule inhibitors of the channel have been identified using both high-throughput screening and in silico methods. These inhibitors show promise in terms of both improved selectivity for KNa1.1 and efficacy in suppressing hyperexcitable neurons. Gain-of-function (GOF) pathogenic variants of KCNT1, the gene encoding the largest known potassium channel subunit, KNa1.1, are associated with developmental and epileptic encephalopathies accompanied by severe psychomotor and intellectual disabilities. Blocking hyperexcitable KNa1.1 channels with quinidine, a class I antiarrhythmic drug, has shown variable success in patients in part because of dose-limiting off-target effects, poor blood–brain barrier (BBB) penetration, and low potency. In recent years, high-resolution cryogenic electron microscopy (cryo-EM) structures of the chicken KNa1.1 channel in different activation states have been determined, and animal models of the diseases have been generated. Alongside increasing information about the functional effects of GOF pathogenic variants on KNa1.1 channel behaviour and how they lead to hyperexcitability, these tools will facilitate the development of more effective treatment strategies. We review the range of KCNT1 variants and their functional effects, the challenges posed by current treatment strategies, and recent advances in finding more potent and selective therapeutic interventions for KCNT1-related epilepsies. Gain-of-function (GOF) pathogenic variants of KCNT1, the gene encoding the largest known potassium channel subunit, KNa1.1, are associated with developmental and epileptic encephalopathies accompanied by severe psychomotor and intellectual disabilities. Blocking hyperexcitable KNa1.1 channels with quinidine, a class I antiarrhythmic drug, has shown variable success in patients in part because of dose-limiting off-target effects, poor blood–brain barrier (BBB) penetration, and low potency. In recent years, high-resolution cryogenic electron microscopy (cryo-EM) structures of the chicken KNa1.1 channel in different activation states have been determined, and animal models of the diseases have been generated. Alongside increasing information about the functional effects of GOF pathogenic variants on KNa1.1 channel behaviour and how they lead to hyperexcitability, these tools will facilitate the development of more effective treatment strategies. We review the range of KCNT1 variants and their functional effects, the challenges posed by current treatment strategies, and recent advances in finding more potent and selective therapeutic interventions for KCNT1-related epilepsies. repolarisation of the membrane potential following an action potential or burst of action potentials. The membrane potential falls below the resting membrane potential, and this is usually facilitated by K+ channel activation. in K+ channels gated by a hydrophobic gate, water transitions between liquid and vapour states within the pore as it interacts with hydrophobic pore-lining residues. In the vapour state, the pore cavity becomes 'de-wetted' or collapsed, and this acts as a barrier to ion permeation. De-wetting is dependent on pore diameter. a computer-aided drug screening technique that identifies structurally similar compounds to a known ligand from a chemical library. These structurally similar compounds can later be docked into the protein of interest and ranked based on predicted binding affinity. on an electrocardiogram (ECG), the QT interval is defined as the time interval between the start of the Q wave and the end of the T wave. This represents the onset of depolarisation and the end of repolarisation of the cardiac action potential. a high-throughput technique for screening large libraries of compounds for K+ channel modulation by exploiting the ability of Rb+ to permeate the channels. Cells are preincubated with 86RbCl and the degree of efflux during the assay is determined by liquid scintillation. Alternatively, cells can be loaded with cold RbCl and the efflux determined by atomic absorption. the canonical mechanism of K+ channel gating. The cytoplasmic end of the S6 helices of K+ channel subunits converge at the bottom of the pore-forming region, forming a 'bundle crossing'. Ion conduction is physically occluded by the S6 helix bundle-crossing, and widening enables ion conduction. a recently identified mechanism of K+ channel gating. The selectivity filter widens as a result of allosteric coupling with the activation gate, facilitated by pore-lining transmembrane helices, to enable ion conduction. a computer-aided drug-screening approach involving docking compounds from a chemical library into a protein structure. Intermolecular interactions can be predicted, and chemicals are ranked based on their predicted binding affinities. a fluorescence-based assay that utilises the permeability of TI+ through K+ channels to detect modulators of K+ channels that are heterologously expressed in mammalian cells. This is a high-throughput technique that can be used to screen large libraries of compounds. associated with prolongation of the QT interval, this acquired or inherited arrhythmia is characterised by 'twisting' of the QRS segment of an ECG. Torsades de Pointes can sometimes lead to ventricular fibrillation and cardiac arrest.