复旦大学屈前辉等研究人员合作揭示VMAT2介导的突触小泡装载单胺类物质的运输和抑制机制。该研究于2024年1月2日在线发表于国际一流学术期刊《细胞研究》。

研究人员表示，血清素和多巴胺等单胺类神经递质通过囊泡单胺转运体 2（VMAT2）进入突触囊泡储存，然后在神经元中释放。VMAT2功能受损是各种神经精神疾病的根源。VMAT2抑制剂瑞舍平（reserpine）和四苯丙胺（tetrabenazine）可用于治疗高血压、与亨廷顿氏症相关的运动障碍和迟发性运动障碍。尽管VMAT2具有重要的生理和药理作用，但其底物识别和被各种抑制剂抑制的结构基础仍然未知。

研究人员展示了人类apo VMAT2的冷冻电镜结构，以及与血清素、四苯丙嗪和瑞舍平结合的状态。这些结构共同捕捉到了三种状态，即面向管腔、闭塞和面向细胞膜的构象。值得注意的是，四苯嗪诱导了TM2和TM7的大幅重排，超出了典型的摇臂开关运动。这些功能动态快照辅以生化分析，揭示了负责配体识别的重要成分，阐明了质子驱动的交换循环，并为设计针对VMAT2的改良药物提供了一个框架。

附：英文原文

Title: Transport and inhibition mechanism for VMAT2-mediated synaptic vesicle loading of monoamines

Author: Wang, Yuwei, Zhang, Pei, Chao, Yulin, Zhu, Zhini, Yang, Chuanhui, Zhou, Zixuan, Li, Yaohui, Long, Yonghui, Liu, Yuehua, Li, Dianfan, Wang, Sheng, Qu, Qianhui

Issue&Volume: 2024-01-02

Abstract: Monoamine neurotransmitters such as serotonin and dopamine are loaded by vesicular monoamine transporter 2 (VMAT2) into synaptic vesicles for storage and subsequent release in neurons. Impaired VMAT2 function underlies various neuropsychiatric diseases. VMAT2 inhibitors reserpine and tetrabenazine are used to treat hypertension, movement disorders associated with Huntington’s Disease and Tardive Dyskinesia. Despite its physiological and pharmacological significance, the structural basis underlying VMAT2 substrate recognition and its inhibition by various inhibitors remains unknown. Here we present cryo-EM structures of human apo VMAT2 in addition to states bound to serotonin, tetrabenazine, and reserpine. These structures collectively capture three states, namely the lumen-facing, occluded, and cytosol-facing conformations. Notably, tetrabenazine induces a substantial rearrangement of TM2 and TM7, extending beyond the typical rocker-switch movement. These functionally dynamic snapshots, complemented by biochemical analysis, unveil the essential components responsible for ligand recognition, elucidate the proton-driven exchange cycle, and provide a framework to design improved pharmaceutics targeting VMAT2.

DOI: 10.1038/s41422-023-00906-z

Source: https://www.nature.com/articles/s41422-023-00906-z