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Mechanisms of neurotransmitter transport and drug inhibition in human VMAT2

Author

Listed:
  • Shabareesh Pidathala

    (St. Jude Children’s Research Hospital)

  • Shuyun Liao

    (Peking University)

  • Yaxin Dai

    (St. Jude Children’s Research Hospital)

  • Xiao Li

    (St. Jude Children’s Research Hospital)

  • Changkun Long

    (Peking University)

  • Chi-Lun Chang

    (St. Jude Children’s Research Hospital)

  • Zhe Zhang

    (Peking University)

  • Chia-Hsueh Lee

    (St. Jude Children’s Research Hospital)

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 neurotransmission3–5. VMATs are also therapeutic drug targets for a number of different conditions6–9. 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.

Suggested Citation

  • Shabareesh Pidathala & Shuyun Liao & Yaxin Dai & Xiao Li & Changkun Long & Chi-Lun Chang & Zhe Zhang & Chia-Hsueh Lee, 2023. "Mechanisms of neurotransmitter transport and drug inhibition in human VMAT2," Nature, Nature, vol. 623(7989), pages 1086-1092, November.
  • Handle: RePEc:nat:nature:v:623:y:2023:i:7989:d:10.1038_s41586-023-06727-9
    DOI: 10.1038/s41586-023-06727-9
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    Cited by:

    1. Dohyun Im & Mika Jormakka & Narinobu Juge & Jun-ichi Kishikawa & Takayuki Kato & Yukihiko Sugita & Takeshi Noda & Tomoko Uemura & Yuki Shiimura & Takaaki Miyaji & Hidetsugu Asada & So Iwata, 2024. "Neurotransmitter recognition by human vesicular monoamine transporter 2," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    2. Ying Lyu & Chunting Fu & Haiyun Ma & Zhaoming Su & Ziyi Sun & Xiaoming Zhou, 2024. "Engineering of a mammalian VMAT2 for cryo-EM analysis results in non-canonical protein folding," Nature Communications, Nature, vol. 15(1), pages 1-9, December.

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