Lipid Modulation of Ligand-Gated Ion Channels

配体门控离子通道的脂质调节

• 批准号: 10027414
• 负责人: Wayland Wing-Lun Cheng
• 金额: $ 39.38万
• 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/10027414
• 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; design; innovation; insight; ion mobility; membrane model; new therapeutic target; novel strategies; programs

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.

项目摘要/摘要 五聚体配基门控离子通道(PLGIC)介导突触传递，是许多 神经活性药物，是pLGIC活性的变构调节剂。包括磷脂在内的内源性脂质， 脂肪酸和类固醇也是pLGICs的变构调节器，这些脂类的作用是基本的 有助于我们对pLGIC生物学和调控的理解。该项目的长期目标是了解 脂类调节pLGICs的分子机制。我们开发了创新的生物物理和 用生物化学技术检测模式pLGIC菊欧文氏菌的脂质结合和调节 配基门控离子通道(ELIC)，包括天然离子迁移率质谱仪(MS)，功能分析 模型膜，以及共价键修饰/光标记。使用这些技术，我们发现 阴离子磷脂1-棕榈酰基-2-油酰基磷脂酰甘油(POPG)直接与ELIC结合并调节 通过相对于不敏感状态稳定打开来进行通道选通。我们现在建议调查 ELIC和GLIC两种模型pLGIC的磷脂、脂肪酸和类固醇调节机制 (Gloebacter配体门控离子通道)，重点是阐明相互作用的特异性和位置，以及 脂结合的影响。这项研究计划的总体愿景是开发一个详细的结构模型 PLGICs的脂质调节，包含了不同的 PLGIC。