Development of Light-Gated Ion Channels With Red-Shifted Action Spectra

具有红移作用光谱的光门离子通道的开发

• 批准号: 164463141
• 负责人: Professor Dr. Marcus Elstner
• 金额: --
• 依托单位: Abteilung für Theoretische Chemische Biologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/164463141?language=en
• 关键词: Development; Light; Gated; Ion; Channels

The aim of this project is to reprogram naturally occurring “blind” receptors in such a way that they become sensitive toward light. Using a combination of chemical synthesis and protein engineering, we have been able to convert ionotropic receptors, i.e. ion channels, into photoreceptors. These can be used to control neural activity and behavior in living organisms. Herein, we propose to investigate our most successful system, the light-actuated ionotropic glutamate receptor (LiGluR), at the atomic level using X-ray crystallography (in collaboration with I. Schlichting) and with molecular dynamics simulations. LiGluR is based on kainate receptors (iGluR6), whose extracellular ligand-binding domain is conjugated to an azobenzene that terminates in a glutamate ligand. Photochemical switching between the extended and bent form of this molecule changes the effective concentration of the ligand, allowing for optical control of the receptor. We believe that this concept is very general and could be easily applied to metabotropic glutamate receptors as well. Together with A. Gottschalk, we will also apply it to pentameric ligand gated ion channels, such as certain nicotinic acetylcholine receptors found in C. elegans. Detailed biophysical investigations of this system will be subsequently carried out in collaboration with J. Heberle. The optimized lightgated glutamate and acetylcholine receptors will be used by our collaborators S. Ryu and A. Gottschalk to address neurobiological questions in zebrafish and nematodes (C. elegans).

该项目的目的是重新编程自然产生的“盲”受体，使其对光线敏感。使用化学合成和蛋白质工程的组合，我们已经能够将离子型受体（即离子通道）转化为光受体。这些可以用来控制生物体的神经活动和行为。在此，我们建议研究我们最成功的系统，光致离子型谷氨酸受体（LiGluR），在原子水平上使用X射线晶体学（与I。Schlichting）和分子动力学模拟。LiGluR基于红藻氨酸受体（iGluR6），其胞外配体结合结构域与终止于谷氨酸配体的偶氮苯缀合。这种分子的延伸和弯曲形式之间的光化学转换改变了配体的有效浓度，允许对受体进行光学控制。我们相信，这一概念是非常普遍的，也可以很容易地应用于代谢型谷氨酸受体。与A. Gottschalk，我们也将其应用于五聚体配体门控离子通道，如在C.优美的随后将与J.Heberle合作对该系统进行详细的生物物理研究。优化的光门控谷氨酸和乙酰胆碱受体将被我们的合作者S。Ryu和A. Gottschalk解决斑马鱼和线虫的神经生物学问题（C。elegans）。