Lipid Modulation of Ligand-Gated Ion Channels

配体门控离子通道的脂质调节

• 批准号: 10645076
• 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/10645076
• 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.

项目概要/摘要 五聚体配体门控离子通道 (pLGIC) 介导突触传递，是许多药物的靶标 神经活性药物，是 pLGIC 活性的变构调节剂。内源性脂质包括磷脂、 脂肪酸和类固醇也是 pLGIC 的变构调节剂，这些脂质的作用至关重要 加深我们对 pLGIC 生物学和调控的理解。该项目的长期目标是了解 脂质调节 pLGIC 的分子机制。我们开发了创新的生物物理和 生化技术检查 pLGIC 模型（菊欧文氏菌）中的脂质结合和调节 配体门控离子通道 (ELIC)，包括天然离子淌度质谱 (MS)、功能分析 模型膜和共价修饰/光标记。使用这些技术，我们发现 阴离子磷脂，1-棕榈酰-2-油酰-磷脂酰甘油 (POPG)，直接结合 ELIC 并进行调节 通过相对于脱敏状态稳定开放来进行通道选通。我们现在建议调查 两种模型 pLGIC（ELIC 和 GLIC）的磷脂、脂肪酸和类固醇调节机制 （Gloeobacter配体门控离子通道），重点是阐明相互作用的特异性和位点，以及 脂质结合的影响。该研究计划的总体愿景是开发详细的结构模型 pLGIC 的脂质调节，涵盖了不同细胞中存在的机制的潜在多样性 pLGIC。

项目成果

Lipid nanodisc scaffold and size alter the structure of a pentameric ligand-gated ion channel.

• DOI: 10.1038/s41467-023-44366-w
• 发表时间: 2024-01-02
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Dalal, Vikram;Arcario, Mark J.;Petroff II, John T.;Tan, Brandon K.;Dietzen, Noah M.;Rau, Michael J.;Fitzpatrick, James A. J.;Brannigan, Grace;Cheng, Wayland W. L.
• 通讯作者: Cheng, Wayland W. L.

Membrane phospholipids control gating of the mechanosensitive potassium leak channel TREK1.

• DOI: 10.1038/s41467-023-36765-w
• 发表时间: 2023-02-25
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Schmidpeter, Philipp A. M.;Petroff, John T.;Khajoueinejad, Leila;Wague, Aboubacar;Frankfater, Cheryl;Cheng, Wayland W. L.;Nimigean, Crina M.;Riegelhaupt, Paul M.
• 通讯作者: Riegelhaupt, Paul M.

Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels.

• DOI: 10.3389/fphys.2021.798102
• 发表时间: 2021
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Cheng WWL;Arcario MJ;Petroff JT 2nd
• 通讯作者: Petroff JT 2nd