Mechanism of calcium potentiation of alpha7 nicotinic receptors

α7烟碱受体钙增强机制

• 批准号: 9296195
• 负责人: Steven M Sine
• 金额: $ 39.53万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9296195
• 关键词: Agonist; Alzheimer' s Disease; Amino Acids; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Attention; Attentional deficit; Barium; Binding Sites; Biological; Biophysics; Brain; Calcium; Calcium Binding; Calcium ion; Cell physiology; Chemicals; Chemosensitization; Chimera organism; Cholinergic Receptors; Cognition; Complement; Coupled; Coupling; Crystallization; Diffusion; Disease; Divalent Cations; Drug Design; Electrophysiology (science); Elements; Extracellular Space; Family; Fingerprint; Foundations; Gated Ion Channel; Goals; Human; Inflammatory; Ion Channel Gating; Ions; Kinetics; Ligand Binding; Ligand Binding Domain; Ligands; Measurement; Measures; Mediating; Mental disorders; Methods; Molecular; Mutagenesis; Mutate; Nerve; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Neuropil; Neurotransmitters; Nicotinic Receptors; Parkinson Disease; Pathologic; Pathway interactions; Physiological; Regulation; Research; Resolution; Rewards; Roentgen Rays; Schizophrenia; Sensory; Sepsis; Short-Term Memory; Signal Transduction; Signaling Molecule; Structure; Testing; Therapeutic; Time; base; cholinergic; drug development; extracellular; insight; nervous system disorder; patch clamp; receptor; receptor function; response; single molecule; stoichiometry; therapeutic development; transmission process

PROJECT SUMMARY- 7 nicotinic receptors are widely distributed throughout the human brain, and are enriched in regions required for cognition, sensory processing, attention, working memory and reward. They have been implicated in neurodegenerative diseases such as Alzheimer’s and Parkinson’s and psychiatric diseases such as schizophrenia, and disorders of attention and cognition. 7 receptors are also present in non-neuronal cells where they contribute to a variety of anti-inflammatory pathways. The overall goal of the proposed research is to develop a mechanistic understanding of activation and modulation of 7 receptors applicable to therapeutic drug design. This proposal will investigate how calcium potentiates 7 nicotinic receptors activated by the low agonist concentrations that prevail physiologically. We have developed a co- agonist hypothesis that not only can explain how 7 signals despite being far from cholinergic nerve terminals, but it also suggests calcium fluctuations associated with neuronal firing regulate 7 signaling. To investigate calcium potentiation of 7, X-ray crystallographic methods will be used to determine atomic resolution structures of an 7 ligand binding domain bound with the potentiating ions calcium and barium. In parallel, single molecule electrophysiological methods will define the kinetic mechanism behind divalent ion potentiation. Finally, application of molecular biological and single molecule electrophysiological methods will identify amino acid residues in 7 that mediate divalent cation potentiation, and determine the stoichiometry with which divalent cations potentiate. Completion of this project will reveal mechanistic underpinnings of activation and calcium regulation of 7 applicable to neurological disease treatment and therapeutic drug design.

项目摘要 - 7 烟碱受体广泛分布在整个人脑中，并且 丰富了认知、感觉处理、注意力、工作记忆和奖励所需的区域。他们 与阿尔茨海默氏症、帕金森氏症等神经退行性疾病以及精神疾病有关 精神分裂症等疾病以及注意力和认知障碍。 α7 受体也存在于 非神经元细胞，它们有助于多种抗炎途径。该项目的总体目标是 拟议的研究旨在从机制上理解 α7 受体的激活和调节 适用于治疗药物设计。该提案将研究钙如何增强 7 烟碱 受体被生理上普遍存在的低激动剂浓度激活。我们开发了一个合作 激动剂假说不仅可以解释 7 在远离胆碱能神经的情况下如何发出信号 末端，但它也表明与神经元放电相关的钙波动调节 α7 信号传导。到 研究α7的钙增强作用，X射线晶体学方法将用于确定原子 与增强离子钙和钡结合的 α7 配体结合域的解析结构。在 平行的单分子电生理学方法将定义二价离子背后的动力学机制 增强作用。最后，分子生物学和单分子电生理学方法的应用将 识别 α7 中介导二价阳离子增强的氨基酸残基，并确定化学计量 二价阳离子可与之增强。该项目的完成将揭示以下机制的基础 α7的激活和钙调节适用于神经系统疾病治疗和治疗药物 设计。