小柯机器人

美国圣裘德儿童研究医院Chia-Hsueh Lee等研究人员合作揭示人类VMAT2的神经递质转运和药物抑制机制。这一研究成果于2023年11月1日在线发表在国际学术期刊《自然》上。

研究人员表示，多巴胺和血清素等单胺类神经递质控制着重要的大脑通路，包括运动、睡眠、奖赏和情绪。单胺能回路的功能障碍与多种神经退行性疾病和神经精神疾病有关。囊泡单胺转运体（VMAT）将单胺包装到囊泡中以便突触释放，对神经传递至关重要。VMAT也是多种不同疾病的治疗药物靶点。尽管这些转运体非常重要，但VMAT的底物转运和药物抑制机制却一直难以捉摸。

研究人员报告了人类囊泡单胺转运体VMAT2与抗胆碱药物丁苯那嗪、抗高血压药物利血平或底物血清素复合物的冷冻电镜结构。值得注意的是，这两种药物的抑制机制完全不同。丁苯那嗪以面向管腔的构象与VMAT2结合，将管腔的门盖锁定在闭锁状态，从而阻止转运循环。与此相反，利血平以面向细胞质的构象与VMAT2结合，扩大了前庭，阻止了底物的进入。对VMAT2的结构分析还揭示了转运体异构化后的构象变化，这种变化推动底物转运进入囊泡。这些发现为理解突触囊泡转运体包装神经递质的生理学和药理学提供了一个结构框架。

附：英文原文

Title: Mechanisms of neurotransmitter transport and drug inhibition in human VMAT2

Author: Pidathala, Shabareesh, Liao, Shuyun, Dai, Yaxin, Li, Xiao, Long, Changkun, Chang, Chi-Lun, Zhang, Zhe, Lee, Chia-Hsueh

Issue&Volume: 2023-11-01

Abstract: Monoamine neurotransmitters such as dopamine and serotonin control important brain pathways, including movement, sleep, reward and mood1. Dysfunction of monoaminergic circuits has been implicated in various neurodegenerative and neuropsychiatric disorders2. Vesicular monoamine transporters (VMATs) pack monoamines into vesicles for synaptic release and are essential to neurotransmission3,4,5. VMATs are also therapeutic drug targets for a number of different conditions6,7,8,9. Despite the importance of these transporters, the mechanisms of substrate transport and drug inhibition of VMATs have remained elusive. Here we report cryo-electron microscopy structures of the human vesicular monoamine transporter VMAT2 in complex with the antichorea drug tetrabenazine, the antihypertensive drug reserpine or the substrate serotonin. Remarkably, the two drugs use completely distinct inhibition mechanisms. Tetrabenazine binds VMAT2 in a lumen-facing conformation, locking the luminal gating lid in an occluded state to arrest the transport cycle. By contrast, reserpine binds in a cytoplasm-facing conformation, expanding the vestibule and blocking substrate access. Structural analyses of VMAT2 also reveal the conformational changes following transporter isomerization that drive substrate transport into the vesicle. These findings provide a structural framework for understanding the physiology and pharmacology of neurotransmitter packaging by synaptic vesicular transporters.

DOI: 10.1038/s41586-023-06727-9

Source: https://www.nature.com/articles/s41586-023-06727-9

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