Selective Blockade of Neuronal BK (α + β4) Channels Preventing Epileptic Seizure

Gain-of-function of BK channels or knockout of their β4 subunit is associated with spontaneous epilepsy. Currently, efficacy of BK (α + β4) channel modulators in preventing epilepsy was never reported. Here, we show that martentoxin selectively inhibits BK (α + β4) channels by interaction with the extracellular loop of the BK β4 subunit (hβ4-loop) at a molar ratio 4:1 (hβ4-loop vs martentoxin). Residues Glu¹⁰⁴, Glu¹²², Gln¹²⁴, Lys¹²⁵, and Glu¹²⁸ of the hβ4-loop form hydrogen bonds with residues Asp⁵, Glu¹³, Lys²⁰, Ser²⁴, Gln²⁶, Lys²⁸, and Arg³⁵ of martentoxin, by which martentoxin reduces the neuronal spiking frequency and increases interspike intervals. Intrahippocampal infusion of martentoxin significantly increases the latency time of seizure, reduces seizure duration and seizure numbers on pentylenetetrazole-induced presensitized rats, inhibits hippocampal hyperexcitability and c-Fos expression, and displays neuroprotective effects on hippocampal neurons. These results suggest that the BK (α + β4) channel is a novel therapeutic target of intractable epilepsy and martentoxin contributes to the rational drug design for epilepsy treatment.