Mechanism of calcium potentiation of alpha7 nicotinic receptors

项目概述-- 丰富的区域需要认知，感觉处理，注意力，工作记忆和奖励。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。H7受体也存在于 非神经元细胞，在那里它们有助于各种抗炎途径。的总体目标 拟议的研究是发展对E177受体的激活和调节的机制理解 适用于治疗药物设计。这项提案将研究钙如何增强尼古丁的吸收， 受生理上普遍存在的低浓度激动剂激活的受体。我们开发了一种合作- 激动剂假说不仅可以解释尽管远离胆碱能神经， 终末，但它也表明与神经元放电相关的钙波动调节β 7信号传导。到 为了研究钙离子增强作用，将使用X射线晶体学方法来确定原子 与增强离子钙和钡结合的β 7配体结合结构域的解析结构。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， 鉴定介导二价阳离子增强作用的MAP 17中的氨基酸残基，并确定化学计量 二价阳离子与其增强。该项目的完成将揭示 适用于神经系统疾病治疗和治疗药物的β 7的活化和钙调节 设计

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.