Montelukast activates β4-containing BK channels and emerges as a pharmacological tool to reduce hippocampal excitability

Large-conductance Ca²⁺- and voltage-activated K⁺ (BK) channels are critical regulators of neuronal excitability and have been implicated in multiple epileptic syndromes. Their functional diversity arises from the co-assembly of pore-forming α-subunits with auxiliary β subunits, among which β4 is highly expressed in distinct regions of the central nervous system, 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 markedly enhanced efficacy in the presence of the β1 and β4 subunits. MTK acts at submicromolar concentrations and facilitates channel opening by altering the energetics of the pore domain, independent of voltage-sensor activation or Ca²⁺ binding to the cytosolic gating ring. In mouse hippocampal slices, MTK reduces intrinsic excitability of DGGCs by decreasing input resistance and enhancing the afterhyperpolarization, effects fully reversed by the BK channel blocker paxilline. Experiments using physiological DGGCs action potential voltage waveforms confirm that MTK enhances subthreshold and evoked BK currents in α/β4 channels as selective targets. Altogether, our findings suggest that MTK, beyond its known anti-inflammatory properties, may modulate neural excitability through direct BK channel activation, offering a novel therapeutic strategy for seizure suppression.