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<p>Serotonin-gated 5-HT3 receptors (5-HT3Rs), which belong to the cys-loop superfamily of ligand-gated ion channels, mediate fast excitatory neurotransmission in the central and peripheral nervous system. They are targets for drugs to treat neurological diseases and psychiatric disorders, as well as chemotherapy-induced and postoperative nausea and emesis. The ever-increasing number of resolved 3D structures of the homopentameric form of 5-HT<sub>3A</sub>R, in combination with new computational approaches allow us to better understand the molecular processes of ligand binding, the subsequent conformational changes, and ion permeation, providing a solid foundation for understanding the biological functions of 5-HT<sub>3A</sub>R and its heteropentameric 5-HT3R homologs. In this review, we first outline the physiological roles and subunit assembly of heteromeric 5-HT3Rs, which predominate in vivo. We then summarize the latest structural insights into the 5-HT<sub>3A</sub>R, revealing details of its architecture, ligand-binding sites, and conformational transitions leading to channel activation. Finally, we discuss the evolving pharmacology of 5-HT3R modulators and provide our perspectives on future research directions aimed at resolving the heteropentameric structures of 5-HT3R in their native membrane and developing modern drugs targeting these receptors.</p>

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The serotonin-gated 5-HT3 receptor: a tale of functions and structures of a prototypical pentameric ligand-gated ion channel

  • 期刊论文

  • 发表日期：

    2026年3月11日

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  • Zhong-jie Ye,
  • Chen-yang Wu,
  • Hang Zhang,
  • Hua-wei Zhang,
  • Horst Vogel

摘要

Serotonin-gated 5-HT3 receptors (5-HT3Rs), which belong to the cys-loop superfamily of ligand-gated ion channels, mediate fast excitatory neurotransmission in the central and peripheral nervous system. They are targets for drugs to treat neurological diseases and psychiatric disorders, as well as chemotherapy-induced and postoperative nausea and emesis. The ever-increasing number of resolved 3D structures of the homopentameric form of 5-HT3AR, in combination with new computational approaches allow us to better understand the molecular processes of ligand binding, the subsequent conformational changes, and ion permeation, providing a solid foundation for understanding the biological functions of 5-HT3AR and its heteropentameric 5-HT3R homologs. In this review, we first outline the physiological roles and subunit assembly of heteromeric 5-HT3Rs, which predominate in vivo. We then summarize the latest structural insights into the 5-HT3AR, revealing details of its architecture, ligand-binding sites, and conformational transitions leading to channel activation. Finally, we discuss the evolving pharmacology of 5-HT3R modulators and provide our perspectives on future research directions aimed at resolving the heteropentameric structures of 5-HT3R in their native membrane and developing modern drugs targeting these receptors.