Montelukast activates BK channels associated with the β4 accessory subunit and emerges as a pharmacological tool to reduce hippocampal excitability

Different β accessory subunits are associated with the large conductance voltage- and Ca2+- dependent K+ channel (BK) in a tissue-specific manner. In particular, BK channel/β4 subunits complexes (α/β4) control neuronal excitability in granule cells of the hippocampal dentate gyrus (GCDG) and, β4 deficient mice display a temporal lobe epilepsy (TLE). Thus, compounds that increase α/β4 activity are of interest for improving epilepsy treatment. Then, based on the β-dependent activating effect of leukotrienes on BK channel, we explore the effect of Montelukast (MTK) on this channel heterologously expressed in HEK cells with or without its β accessory subunits (β1, β2, and β4). MTK is a CysLT1 receptor antagonist used as an anti-asthmatic drug that could share the affinity properties with the leukotrienes. Using the patch-clamp technique we found that MTK shifts the activation curves of α/β1 and α/β4 to more hyperpolarized voltages in a concentration-dependent manner (300 nM MTK: ΔV1/2 (α/β1)= −54.4 ± 8.4 mV; n=6; p<0.05 and ΔV1/2 (α/β4)= −36 ± 13.5 mV; n=5; p<0.05) without affecting α/β2 channel and, only at concentrations greater than 1 µM, slightly shifts the homomeric BK channel curve (ΔV1/2= −10.8 ± 3.7 mV; n=3; p<0.05). MTK delays α/β4 deactivation, suggesting an open channel stabilization (1 µM MTK (−60 mV): τMTK= 27.6 ± 3.7 ms vs. τcontrol= 2.0 ± 0.3 ms n= 5, p<0.05). Finally, as a promising result, we observed that 1 µM MTK decreases the number of action potential spikes induced by 140 pA injection in GCDG from mouse brain slices (58 ± 8%, n=3, p<0.05). Our results indicate that MTK directly activates the α/β4 channel and suggest that it could reduce GCDG excitability and may be a putative new treatment for TLE.