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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam.
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The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam.

机译：突触小泡蛋白SV2A是抗癫痫药左乙拉西坦的结合位点。

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摘要

Here, we show that the synaptic vesicle protein SV2A is the brain binding site of levetiracetam (LEV), a new antiepileptic drug with a unique activity profile in animal models of seizure and epilepsy. The LEV-binding site is enriched in synaptic vesicles, and photoaffinity labeling of purified synaptic vesicles confirms that it has an apparent molecular mass of approximately 90 kDa. Brain membranes and purified synaptic vesicles from mice lacking SV2A do not bind a tritiated LEV derivative, indicating that SV2A is necessary for LEV binding. LEV and related compounds bind to SV2A expressed in fibroblasts, indicating that SV2A is sufficient for LEV binding. No binding was observed to the related isoforms SV2B and SV2C. Furthermore, there is a high degree of correlation between binding affinities of a series of LEV derivatives to SV2A in fibroblasts and to the LEV-binding site in brain. Finally, there is a strong correlation between the affinity of a compound for SV2A and its ability to protect against seizures in an audiogenic mouse animal model of epilepsy. These experimental results suggest that SV2A is the binding site of LEV in the brain and that LEV acts by modulating the function of SV2A, supporting previous indications that LEV possesses a mechanism of action distinct from that of other antiepileptic drugs. Further, these results indicate that proteins involved in vesicle exocytosis, and SV2 in particular, are promising targets for the development of new CNS drug therapies.
机译：在这里，我们显示突触小泡蛋白SV2A是左乙拉西坦（LEV）的大脑结合位点，左乙拉西坦是一种新型的抗癫痫药，在癫痫和癫痫动物模型中具有独特的活性。 LEV结合位点富含突触小泡，纯化的突触小泡的光亲和标记证实其表观分子量约为90 kDa。来自缺少SV2A的小鼠的脑膜和纯化的突触小泡不结合a化的LEV衍生物，表明SV2A是LEV结合所必需的。 LEV和相关化合物与成纤维细胞中表达的SV2A结合，表明SV2A足以与LEV结合。没有观察到与相关同工型SV2B和SV2C的结合。此外，一系列LEV衍生物与成纤维细胞中SV2A的结合亲和力与脑中LEV结合位点之间的亲和力高度相关。最后，在对声源性癫痫的小鼠动物模型中，化合物对SV2A的亲和力与防止癫痫发作的能力之间存在很强的相关性。这些实验结果表明，SV2A是LEV在大脑中的结合位点，并且LEV通过调节SV2A的功能起作用，支持了先前的迹象表明LEV具有不同于其他抗癫痫药的作用机制。此外，这些结果表明，参与囊泡胞吐作用的蛋白质，特别是SV2，是开发新的CNS药物疗法的有希望的目标。

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