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Anticonvulsant effects afforded by a short-chain scorpion toxin selectively targeting BK(α+β4)

Jie Tao  Xinlian Liu  Shuzhang Zhang  Yonghua Ji  Chunyang Cao  
【摘要】:Epilepsy is a common brain disorder affecting round 1% of the population.Large conductance,Ca~(2+)-activated K~+(BK) channels,broadly expressed in the central nervous system,contribute to generating the fast-afterhyperpolarization,which helps set neuronal firing rates at the single-cell as well as network level.Gain-of-function in BK channels or knockout of its β4 subunit,a BK inhibitory subunit enriched in brain,are associated with spontaneous epilepsy in both animal models and humans.So far,no studies on the efficacy of BK(α+β4) channel modulators in preventing epilepsy were reported.In this report,we show that the scorpion toxin martentoxin selectively inhibits BK(α+β4) channel through hydrogen-bond and salt-bridge interactions with the extracellular loop of BK β4 subunit,which represents a novel interaction model between potassium channels and their specific ligands.By this specific inhibition,intrahippocampal infusion of martentoxin significantly increases latency time of seizure,reduces the seizure duration and seizure numbers on pentylenetetrazole-induced pre-sensitized rats,inhibits hippocampal hyperexcitability as well as c-Fos gene expression,and demonstrates neuroprotective effects on hippocampal neurons.These results suggest that BK(α+β4) channel could be regarded as a novel therapeutic target of intractable epilepsy,and martentoxin might contribute to the rational drug-design for epilepsy treatment.

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