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Mechanisms of Neurotransmitter-Gated Ion Channels

神经递质门控离子通道的机制

基本信息

批准号：
10369712
负责人：
CLAUDIO F GROSMAN
金额：
$ 41.11万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10369712
关键词：
ASIC channel Address Adopted Alzheimer&apos s Disease Amino Acid Sequence Anesthetics Animals Anions Benzodiazepines Binding Biological Assay Caliber Cations Cells Charge Chemicals Chimera organism Complement Computer Simulation Computers Congenital Epilepsy Coupled Coupling Cryoelectron Microscopy Crystallization Data Dependence Detergents Drug Design Electrophysiology (science)Electrostatics Equilibrium Extracellular Domain Free Energy Glutamate Receptor Inflammation Invertebrates Ion Channel Ion Channel Gating Ions Knowledge Ligand Binding Ligands Literature Mediating Membrane Modeling Molecular Molecular Conformation Mutation Nature Neurotransmitters Nicotine Outcome P2X-receptor Parents Pharmaceutical Preparations Phospholipids Property Protein Engineering Proteins Recreational Drugs Rewards Role Schizophrenia Side Specificity Structural Models Structure Synapses Synaptic Transmission Testing Transmembrane Domain Ursidae Family Work X-Ray Crystallography alpha helix alpha-bungarotoxin receptor computer studies conformational conversion constriction desensitization diabetic patient in vivo member molecular dynamics mutant nanodisk nervous system disorder novel painful neuropathy patch clamp postsynaptic presynaptic radioligand receptor reconstitution simulation success targeted treatment

项目摘要

The superfamily of pentameric ligand-gated ion channels (pLGICs) is one of the four superfamilies of synaptic ionotropic receptors present in animals; the other three are the excitatory glutamate receptors, the ATP-gated cation channels (P2X), and the acid-sensing ion channels (ASIC). Postsynaptic pLGICs mediate fast synaptic transmission, whereas presynaptic pLGICs modulate the release of other neurotransmitters. In addition, more recently, some pLGICs have been proposed to be involved in non-neuronal phenomena with the most compelling evidence suggesting a role for the α7 nicotinic acetylcholine receptor in inflammation. Importantly, pLGICs are the target of therapeutic drugs (such as benzodiazepines and anesthetics) and recreational drugs (such as nicotine), and their malfunction is often associated with neurological disease—including neuropathic pain in diabetic patients, congenital epilepsy, schizophrenia and Alzheimer's disease. Much is known about the structure and function of these ion channels. However, progress in rational drug design—undoubtedly, a most intriguing and potentially rewarding application of our basic knowledge—has lagged far behind in part because our understanding of how structure gives rise to function in pLGICs remains incomplete. Here, we propose experimental work (electrophysiology, radioligand-binding assays, and direct structural approaches) and computational work (molecular and Brownian dynamics simulations, and electrostatic calculations) that will allow us to: 1) Understand the “coupling” between ligand-binding and gating. We will challenge the prevailing view that the extracellular domain and the transmembrane domain form functionally autonomous units that need to be “coupled” for the channel to function as a whole; 2) Determine the structure of these channels in functionally well-defined states and elucidate the effect of the membrane on their conformational free-energy landscapes; and 3) Characterize the impact of side-chain conformation at the selectivity filter on cation-versus-anion selectivity. Collectively, these three aims cover the three most fundamental aspects of ligand-gated ion channels, namely, ligand binding, gating/desensitization, and ion conduction/charge selectivity.

五聚体配体门控离子通道（pLGICs）超家族是突触传递的四个超家族之一，离子型受体存在于动物;其他三个是兴奋性谷氨酸受体，ATP门控阳离子通道（P2 X）和酸敏感离子通道（ASIC）。突触后pLGIC介导快速突触突触前pLGIC调节其他神经递质的释放。此外，更最近，一些pLGIC被认为与非神经元现象有关，令人信服的证据表明α7烟碱乙酰胆碱受体在炎症中的作用。重要的是， pLGIC是治疗药物（如苯二氮卓类和麻醉剂）和娱乐药物的靶点 (such尼古丁），它们的功能障碍通常与神经系统疾病有关，包括神经性糖尿病患者的疼痛，先天性癫痫，精神分裂症和阿尔茨海默病。多少人知道这些离子通道的结构和功能然而，合理药物设计的进展-毫无疑问，最有趣和潜在的有益的应用我们的基本知识-已经远远落后，部分因为我们对pLGIC的结构如何产生功能的理解仍然不完整。这里我们提出实验工作（电生理学，放射性配体结合测定和直接结构方法）和计算工作（分子和布朗动力学模拟，以及静电计算），将使我们能够：1）理解配体结合和门控之间的“耦合”。我们将挑战细胞外结构域和跨膜结构域形成功能自主的流行观点需要“耦合”的通道作为一个整体运行的单元; 2）确定这些单元的结构通道的功能明确的状态，并阐明其构象的膜的影响自由能景观;和3）表征选择性过滤器处的侧链构象对阳离子对阴离子选择性。总的来说，这三个目标涵盖了以下三个最基本的方面：配体门控离子通道，即配体结合、门控/脱敏和离子传导/电荷选择性

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Block of muscle nicotinic receptors by choline suggests that the activation and desensitization gates act as distinct molecular entities.

胆碱肌肉烟碱受体的块表明，激活和脱敏的门是不同的分子实体。

DOI：
10.1085/jgp.200509437
发表时间：
2006-06
期刊：
The Journal of general physiology
影响因子：
0
作者：
Purohit Y;Grosman C
通讯作者：
Grosman C

Probing function in ligand-gated ion channels without measuring ion transport.

DOI：
10.1085/jgp.202213082
发表时间：
2022-06-06
期刊：
The Journal of general physiology
影响因子：
0
作者：
通讯作者：

An experimental test of the nicotinic hypothesis of COVID-19.

DOI：
10.1073/pnas.2204242119
发表时间：
2022-11
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
通讯作者：

Structure and function at the lipid-protein interface of a pentameric ligand-gated ion channel.

五聚体配体门控离子通道的脂质-蛋白质界面的结构和功能。

DOI：
10.1073/pnas.2100164118
发表时间：
2021
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Kumar,Pramod;Cymes,GiselaD;Grosman,Claudio
通讯作者：
Grosman,Claudio

Tunable pKa values and the basis of opposite charge selectivities in nicotinic-type receptors.