Individual data of MTK effects BK channels associated with the β4 auxiliary subunit

Abstract

Data from Large-conductance Ca²⁺- and voltage-activated K⁺ (BK) channels are key determinants of neuronal excitability and are implicated in multiple epileptic syndromes. Their functional diversity arises from the co-assembly of α-subunits with β auxiliary subunits, among which β4 is highly expressed in specific central nervous system regions, including hippocampal Dentate Gyrus Granule Cells (DGGCs). Here we identify montelukast (MTK), a clinically approved cysteinyl-leukotriene receptor antagonist, as a direct activator of BK channels, with its effect markedly enhanced by the presence of the β4 subunit. MTK acts at submicromolar concentrations, and our mechanistic analysis shows that channel activation results from modulation of pore-domain function without altering voltage-sensor activation or Ca²⁺ binding to the Ca²⁺ sensor domain. In mouse hippocampal slices, MTK reduces DGGCs excitability by decreasing input resistance and enhancing the action potential afterhyperpolarization, effects that are abolished by the BK channel blocker paxilline. Together, our findings demonstrate that MTK is a β4-dependent BK channel activator that reduces hippocampal granule cell excitability. This reveals an unexpected molecular action of a widely used drug and suggests a potential therapeutic strategy for seizure suppression.