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

ORSI, F; MONAT, J; MILESI, V; RAINGO, J; MARTÍN, P

San Diego

Congreso; BPS Annual Meeting 2023; 2023

Bipphysical Society

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