Mechanisms of Neurotransmitter-gated Ion Channels

神经递质门控离子通道的机制

• 批准号: 7373257
• 负责人: CLAUDIO F GROSMAN
• 金额: $ 33.47万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7373257
• 关键词: Acetylcholine; Address; Affect; Affinity; Alzheimer' s Disease; Anions; Apoptosis; Area; Behavior Control; Biology; Brain; Breathing; Cardiovascular Diseases; Cations; Cell Differentiation process; Characteristics; Chemistry; Choline; Cholinergic Agents; Cholinergic Receptors; Chromosome Pairing; Condition; Confusion; Coupling; DNA Sequence Rearrangement; Disease; Electrophysiology (science); Electrostatics; Endothelial Cells; Engineering; Equilibrium; Excision; Gated Ion Channel; Glycine Receptors; Goals; In Situ; In Vitro; Ion Channel; Ions; Kinetics; Knowledge; Lead; Ligands; Location; Lung; Lymphocyte; Malignant Neoplasms; Mediating; Mediator of activation protein; Membrane; Mental Depression; Modeling; Molecular Conformation; Motor; Motor Neurons; Muscle; Mutagenesis; Nature; Neurodegenerative Disorders; Neuromuscular Junction; Neurons; Neurotransmitter Receptor; Neurotransmitters; Nicotine; Nicotine Dependence; Nicotinic Receptors; Nitrosamines; Numbers; Outcome; Patients; Physics; Physiologic pulse; Physiological; Play; Probability; Process; Property; Protein Engineering; Proteins; Pulse taking; Receptor Activation; Relative (related person); Research; Resistance; Risk; Role; Side; Signal Transduction; Slow-Channel Congenital Myasthenic Syndromes; Smoking; 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; keratinocyte; malignant mouth neoplasm; mutant; neuromuscular transmission; neurotransmission; postsynaptic; presynaptic; prevent; receptor; receptor binding; research study; response; serotonin receptor; success; tool; uptake

DESCRIPTION (provided by applicant): 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 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 quantitative 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 wild-type 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 disease. Furthermore, AChRs are also expressed in the airways, keratinocytes, lymphocytes, and endothelial cells where they are mediators of cell differentiation, proliferation, and resistance to apoptosis and, thus, of cancer. Indeed, it is becoming increasingly clear that nicotine addiction (which is caused by the interaction of nicotine with AChRs in behavior- controlling areas of the brain) increases the risk of developing lung and oral cancer owing to the excessive activation of these non-muscle/non-neuronal AChRs by inhaled nicotine and nicotine-derived nitrosamines while smoking.

描述（由申请人提供）：本提案的重点是肌肉尼古丁乙酰胆碱受体（AChR），神经递质门控离子通道，介导脊椎动物神经肌肉接点（NMJ）的快速突触传递。这项提议的主要目的是了解这种受体通道的结构如何产生其功能，以及这种功能如何精确地适应脊椎动物NMJ的生理需求。多年来，对AChR的研究已经为离子通道的物理、化学和生物学方面的基本问题提供了答案，这些问题无法用（可能）任何其他通道解决。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：1)确定AChR通道的位置和物理性质，以及通道打开和关闭时的重排；2)了解AChR选择性过滤器的结构和功能之间的关系，以及离子占据与门控/脱敏之间的耦合；3)估计野生型AChR的无配体门控平衡常数的值；4)定义脱敏对AChR突触反应的贡献。值得注意的是，ACh、AChR和NMJ除了在神经元到肌肉信号的传递中具有明显的相关性外，通常还可以作为神经递质、受体和突触的模型。因此，从实验中获得的知识将对我们对突触后受体和快速突触传递的基本理解产生广泛的影响。还应该强调的是，achr介导的神经传递不仅支持运动功能，也支持自主神经和认知功能，因此，它不仅在肌无力中受到损害，而且在心血管疾病和神经退行性疾病（如阿尔茨海默病）中也受到损害。此外，achr也在气道、角化细胞、淋巴细胞和内皮细胞中表达，它们是细胞分化、增殖和抗凋亡的介质，因此也是癌症的介质。事实上，越来越清楚的是，尼古丁成瘾（由尼古丁与大脑行为控制区域的achr相互作用引起）增加了患肺癌和口腔癌的风险，因为吸烟时吸入尼古丁和尼古丁衍生的亚硝胺会过度激活这些非肌肉/非神经元的achr。