Lipid Modulation of Ligand-Gated Ion Channels

配体门控离子通道的脂质调节

• 批准号: 10582362
• 负责人: Wayland Wing-Lun Cheng
• 金额: $ 10.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582362
• 关键词: Anesthetics; Antiepileptic Agents; Binding; Biochemical; Biology; Biophysics; Fatty Acids; Goals; Ion Channel Gating; Ligands; Lipid Binding; Lipids; Mass Spectrum Analysis; Mediating; Modeling; Modification; Molecular; Nootropic Agents; Pectobacterium chrysanthemi; Pharmaceutical Preparations; Phosphatidylglycerols; Phospholipids; Regulation; Research; Site; Specificity; Steroids; Structural Models; Synaptic Transmission; Techniques; Vision; desensitization; innovation; insight; ion mobility; membrane model; new therapeutic target; novel strategies; programs; rational design

Project Summary/Abstract Pentameric ligand-gated ion channels (pLGICs) mediate synaptic transmission and are the targets of many neuroactive drugs, which are allosteric modulators of pLGIC activity. Endogenous lipids including phospholipids, fatty acids and steroids are also allosteric modulators of pLGICs, and the effects of these lipids are fundamental to our understanding of pLGIC biology and regulation. The long-term goal of this project is to understand the molecular mechanisms by which lipids modulate pLGICs. We have developed innovative biophysical and biochemical techniques to examine lipid binding and modulation in the model pLGIC, Erwinia chrysanthemi ligand-gated ion channel (ELIC), including native ion mobility mass spectrometry (MS), functional analysis in model membranes, and covalent modification/photolabeling. Using these techniques, we discovered that the anionic phospholipid, 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), directly binds to ELIC and modulates channel gating by stabilizing the open relative to the desensitized state. We now propose to investigate the mechanisms of phospholipid, fatty acid and steroid modulation of two model pLGICs, ELIC and GLIC (Gloeobacter ligand-gated ion channel), with a focus on elucidating the specificity and sites of interaction, and the effects of lipid binding. The overall vision of this research program is to develop a detailed structural model of lipid modulation of pLGICs that encompasses the potential diversity of mechanisms present in different pLGICs.

项目总结/文摘