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NMR studies on the mechanism of selective blockade of neuronal BK(α+β4) channel preventing epileptic seizure

Xinlian Liu  Jie Tao  Shuzhang Zhang  Wenxian Lan  Chunxi Wang  Yonghua Ji  Chunyang Cao  
【摘要】:Large conductance,Ca~(2+)-and voltage activated K+(BK) channels,broadly expressed in central nervous system,contribute to generating fast-afterhyperpolarization,which helps set neuronal firing rates at single-cell as well as network level.Gain-of-function in BK channels or knockout of its β4 subunit is associated with spontaneous epilepsy.Currently,efficacy of BK(α+β4) channel modulators in preventing epilepsy were never reported.Here,mainly by nuclear magnetic resonance,we show that martentoxin selectively inhibits BK(α+β4) channel through hydrogen-bond interactions with the extracellular loop of BK channel β4 subunit.By this inhibition,intrahippocampal infusion of martentoxin significantly increases latency time of seizure,reduces seizure duration and seizure numbers on pentylenetetrazole-induced pre-sensitized rats,inhibits hippocampal hyperexcitability as well as c-Fos expression,and displays neuroprotective effects on hippocampal neurons.These results suggest that BK(α+β4) channel can be regarded as a novel therapeutic target of intractable epilepsy,and martentoxin contributes to the rational drug-design for epilepsy treatment.

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