Cannabidiol interactions with voltage-gated sodium channels.
Cannabidiol interactions with voltage-gated sodium channels.
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DOI：
10.7554/elife.58593
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发表时间：
2020-10-22
期刊：
影响因子：
7.7
通讯作者：
Wallace BA
中科院分区：
文献类型：
--
作者：
Sait LG;Sula A;Ghovanloo MR;Hollingworth D;Ruben PC;Wallace BA
电压门控钠通道是为治疗神经系统疾病而开发的一系列药物的靶点。大麻二酚（CBD）是一种从大麻植物中分离出来的非精神活性化合物，最近被批准用于治疗与钠通道突变相关的两种类型的癫痫。该研究使用高分辨率X射线晶体学来证明CBD和NavMs电压门控钠通道之间相互作用的详细性质，以及电生理学来显示CBD与这些通道结合的功能效应。CBD在开窗和通道的中央疏水腔的界面处的新位点处结合。在该位点的结合阻断跨膜钠离子转运途径，提供了通道抑制的分子机制。模拟研究表明，为什么密切相关的精神活性化合物四氢大麻酚可能对这些通道没有相同的影响。最后，与TRPV2通道，最近也提出了CBD的目标网站进行了比较。总之，这项研究为CBD与钠通道相互作用的可能机制提供了新的见解。
Voltage-gated sodium channels are targets for a range of pharmaceutical drugs developed for the treatment of neurological diseases. Cannabidiol (CBD), the non-psychoactive compound isolated from cannabis plants, was recently approved for treatment of two types of epilepsy associated with sodium channel mutations. This study used high-resolution X-ray crystallography to demonstrate the detailed nature of the interactions between CBD and the NavMs voltage-gated sodium channel, and electrophysiology to show the functional effects of binding CBD to these channels. CBD binds at a novel site at the interface of the fenestrations and the central hydrophobic cavity of the channel. Binding at this site blocks the transmembrane-spanning sodium ion translocation pathway, providing a molecular mechanism for channel inhibition. Modelling studies suggest why the closely-related psychoactive compound tetrahydrocannabinol may not have the same effects on these channels. Finally, comparisons are made with the TRPV2 channel, also recently proposed as a target site for CBD. In summary, this study provides novel insight into a possible mechanism for CBD interactions with sodium channels.