Mechanisms of Neurotransmitter-gated Ion Channels

神经递质门控离子通道的机制

• 批准号: 7415296
• 负责人: CLAUDIO F GROSMAN
• 金额: $ 37.79万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7415296
• 关键词: Acetylcholine; Action Potentials; Address; Affect; Affinity; Alzheimer' s Disease; Anions; Biology; Cardiovascular Diseases; Cations; Characteristics; Chemistry; Choline; Cholinergic Agents; Cholinergic Receptors; Chromosome Pairing; Condition; Confusion; Coupling; DNA Sequence Rearrangement; Disease; Electrophysiology (science); Electrostatics; Engineering; Equilibrium; Excision; Gated Ion Channel; Glycine Receptors; Goals; In Situ; In Vitro; Ion Channel; Ion Channel Gating; Ions; Kinetics; Knowledge; Lead; Ligands; Location; Mediating; Membrane; Mental Depression; Modeling; Molecular Conformation; Motor; Motor Neurons; Muscle; Mutagenesis; Nature; Neurodegenerative Disorders; Neuromuscular Junction; Neurons; Neurotransmitter Receptor; Neurotransmitters; Nicotinic Receptors; Numbers; Outcome; Patients; Physics; Physiologic pulse; Physiological; Play; Probability; Process; Property; Protein Engineering; Proteins; Pulse taking; Receptor Activation; Relative (related person); Research; Research Personnel; Role; Side; Signal Transduction; Slow-Channel Congenital Myasthenic Syndromes; Structure; Structure-Activity Relationship; Suggestion; Synapses; Synaptic Cleft; Synaptic Transmission; Testing; Thinking; Time; Training; Vertebral column; choline transporter; cholinergic; cognitive function; defined contribution; desensitization; design; gain of function; gamma-Aminobutyric Acid; mutant; neuromuscular transmission; neurotransmission; postsynaptic; presynaptic; prevent; receptor; receptor binding; research study; response; serotonin receptor; success; tool; uptake

The focus of this proposal is the muscle nicotinic acetylcholine receptor (AChR), the neurotransmitter-gated ion channel that mediates fast synaptic transmission at the vertebrate neuromuscular junction (NMJ). The broad objective of this proposal is to understand how the structure of this receptor-channel gives rise to its function, and how this function is exquisitely tailored to the physiological needs of the the vertebrate NMJ. Throughout the years, research on the AChR has provided answers to fundamental questions on the physics, chemistry, and biology of ion channels that cannot be addressed with (probably) any other channel. Our main tools are single-channel and macroscopic electrophysiology (using both in-vitro and in-situ approaches), protein engineering, and quantitatitive thinking. Our four specific aims are: I) To determine the location and physical nature of the AChR's gate(s), and its rearrangement upon opening and shutting of the channel, II) To understand the relationship between structure and function in the AChR's selectivity filter, and the coupling between ion-occupancy and gating/desensitization, III) To estimate the value of the AChR's unliganded-gating equilibrium constant, and IV) To define the contribution of desensitization to the synaptic response of the AChR . It is worth noting that, in addition to their obvious relevance in the relay of neuron-to-muscle signals, ACh, the AChR, and the NMJ have served as models of neurotransmitters, receptors, and synapses in general. Hence, the knowledge derived from the proposed experiments is poised to have a broad impact on our basic understanding of postsynaptic receptors and fast synaptic transmission. It should also be emphasized that AChR-mediated neurotransmission supports not only motor but, also, autonomic and cognitive function and, therefore, that it is compromised not only in myasthenias but, also, in cardiovascular diseases and neurodegenerative disorders such as Alzheimer's disease.

这项建议的重点是肌肉烟碱乙酰胆碱受体（AChR），神经递质门控 在脊椎动物神经肌肉接头（NMJ）介导快速突触传递的离子通道。的 这项建议的广泛目标是了解这种受体通道的结构如何引起其 功能，以及该功能如何根据脊椎动物NMJ的生理需求进行精心定制。 多年来，对乙酰胆碱受体的研究为人类的基本问题提供了答案。 离子通道的物理、化学和生物学，（可能）无法用任何其他方法解决。 频道我们的主要工具是单通道和宏观电生理学（使用体外和 原位方法），蛋白质工程和定量思维。我们的四个具体目标是： 确定AChR门的位置和物理性质，以及打开后的重新排列， 了解AChR的结构与功能之间的关系， 选择性过滤器，以及离子占有率和门控/脱敏之间的耦合，III）为了估计 的AChR的unliganded-gating平衡常数的值，和IV）为了定义的贡献， 对乙酰胆碱受体的突触反应脱敏。值得注意的是，除了明显的 在神经元到肌肉信号的传递中，ACh，AChR和NMJ都是神经元到肌肉信号传递的模型。 神经递质受体和突触。因此，从建议中获得的知识 实验准备对我们对突触后受体的基本理解产生广泛的影响， 快速突触传递还应该强调的是，乙酰胆碱受体介导的神经传递支持 不仅是运动功能，还有自主神经和认知功能，因此，它不仅在 肌无力症，但也在心血管疾病和神经退行性疾病，如阿尔茨海默氏症， 疾病