Differential modulation of BK channels by simvastatin: Critical role of the auxiliary β4 subunit

Simvastatin has neuroprotective effects in neurological disorders; yet its mechanisms remain incompletely elucidated. Large-conductance calcium-activated potassium (BK) channels, containing the brain-enriched β4 subunits, are implicated in neurological disorders and represent a potential target for simvastatin. Although simvastatin bidirectionally modulates vascular β1 subunit-containing BK channels, its direct effects, calcium dependence and specificity for neuronal β4-containing BK channels remain unclear.

Different BK channel plasmids were heterologously expressed in HEK293T cells, and channel currents were recorded using an inside-out patch clamp configuration. Epilepsy was induced in mice using pilocarpine and assessed through combined Racine scale behavioural analysis and electroencephalographic recordings.

Simvastatin directly modulates BKα channels in a calcium-dependent manner. Two Ca²⁺-binding sites mediate this interaction. Simvastatin potently enhances the activity of BKαβ4 channels both with and without 1 μM [Ca²⁺]_i. Additionally, simvastatin mitigates pilocarpine-induced epileptic behaviour in female ICR mice in a dose-dependent manner, which the BK channel blocker paxilline can reverse.

This study identifies BK channel modulation as a novel mechanism underlying simvastatin's neuroprotective effects. β4-containing BK channels are a molecular target of simvastatin in vitro, and their activation profile aligns with simvastatin's anti-seizure effects in vivo. These findings provide a molecular basis for repurposing statins and developing targeted therapies for neurological disorders.