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Pentameric ligand-gated ion channels (pLGICs) are a family of cation- and anion-selective channels that mediate fast synaptic transmission and regulate excitability in the nervous system. They include the GABA(A) receptor, nicotinic acetylcholine receptor (nAChR), glycine receptor (GlyR), and serotonin receptor (5-HT3AR). pLGICs are gated by neurotransmitters, such as GABA and acetylcholine, producing rapid activation and slow desensitization. They are also modulated by lipids, including anionic phospholipids, cholesterol, and fatty acids. Here, we examine recent cryo-electron microscopy structures of pLGICs that reveal the molecular basis of ligand binding, activation, and desensitization. These structures have enabled the application of computational techniques, providing additional insight into structure–function relationships. We present how these approaches have informed the location of the activation and desensitization gates, the pathways of ion conduction, and the sites and energetics of ligand and lipid interactions.

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Structure–Function Studies of Pentameric Ligand-Gated Ion Channels: Combining Experimental and Computational Approaches

  • 章节

  • 发表日期：

    2026年

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  • Wayland W. L. Cheng,
  • Mark J. Arcario

摘要

Pentameric ligand-gated ion channels (pLGICs) are a family of cation- and anion-selective channels that mediate fast synaptic transmission and regulate excitability in the nervous system. They include the GABA(A) receptor, nicotinic acetylcholine receptor (nAChR), glycine receptor (GlyR), and serotonin receptor (5-HT3AR). pLGICs are gated by neurotransmitters, such as GABA and acetylcholine, producing rapid activation and slow desensitization. They are also modulated by lipids, including anionic phospholipids, cholesterol, and fatty acids. Here, we examine recent cryo-electron microscopy structures of pLGICs that reveal the molecular basis of ligand binding, activation, and desensitization. These structures have enabled the application of computational techniques, providing additional insight into structure–function relationships. We present how these approaches have informed the location of the activation and desensitization gates, the pathways of ion conduction, and the sites and energetics of ligand and lipid interactions.