Allosteric Modulation in Nicotinic Acetylcholine Receptors

烟碱乙酰胆碱受体的变构调节

• 批准号: 2204419
• 负责人: Mark Levandoski
• 金额: $ 12.37万
• 依托单位: Grinnell College
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2204419&HistoricalAwards=false
• 关键词: Allosteric; Modulation; Nicotinic; Acetylcholine; Receptors

With support from the Chemistry of Life Processes Program in the Chemistry Divisio, Dr. Mark Levandoski of Grinnell College will investigate how nicotinic acetylcholine receptors respond to neurotransmitters, chemical signals that control how cells communicate with each other throughout the nervous system. These receptors change their shapes to control the passage of charged particles into muscle cells and neurons. This project will use high level computational methods to study how these shape changes are affected by acetylcholine, a neurotransmitter found naturally in the body, or nicotine, one that comes from use of tobacco products. The project provides research opportunities and mentoring to undergraduate students and, as a result, is expected to increase access to the sciences for students traditionally underrepresented in STEM (science, technology, engineering and mathematics) fields, improve STEM education, and contribute to a more diverse, global STEM workforce.Nicotinic acetylcholine receptors play important roles in higher order brain functions such as memory, attention and motor control. These receptors have been intensely studied, making them foundational exemplars of a very large family of ligand-gated ion channels. Dr. Levandoski’s research has focused for two decades on the actions of small molecules that modulate the receptor state transitions without activating the system themselves, compounds that work like molecular rheostats. This project will apply molecular dynamics simulations to elucidate local structural elements in the receptor binding sites and how model allosteric modulators effect global changes that transform modulator binding into channel gating. The results from these simulations will allow molecular interpretation of the large body of functional electrophysiology data from the PI’s lab and others. This project aims to provide a comprehensive view of how a full-length, heteromeric nicotinic receptor interacts with allosteric modulators.This project is jointly funded by Chemistry of Life Processes Program and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学Diablo生命过程计划的化学的支持下，格林内尔学院的Mark Levandoski博士将研究烟碱乙酰胆碱受体如何对神经递质做出反应，这些神经递质是控制细胞如何在整个神经系统中相互交流的化学信号。这些受体改变它们的形状来控制带电粒子进入肌肉细胞和神经元的通道。该项目将使用高级计算方法来研究这些形状变化如何受到乙酰胆碱（一种在体内天然存在的神经递质）或尼古丁（一种来自烟草产品的使用）的影响。该项目为本科生提供研究机会和指导，因此，预计将增加传统上在STEM中代表性不足的学生对科学的接触（科学、技术、工程和数学）领域，改善STEM教育，并为更多样化的全球STEM劳动力做出贡献。烟碱乙酰胆碱受体在更高级的大脑功能中发挥重要作用，如记忆，注意力和运动控制。这些受体已被深入研究，使它们成为配体门控离子通道的一个非常大的家族的基础范例。Levandoski博士的研究集中在小分子的作用上，这些小分子调节受体状态转换而不激活系统本身，这些化合物就像分子变阻器一样工作。该项目将应用分子动力学模拟来阐明受体结合位点的局部结构元素，以及模型变构调节剂如何影响将调节剂结合转化为通道门控的全局变化。从这些模拟的结果将允许从PI的实验室和其他人的功能电生理数据的大机构的分子解释。该项目旨在提供全长异聚烟碱受体如何与变构调节剂相互作用的全面观点。该项目由生命过程化学计划和刺激竞争研究的既定计划（EPSCoR）共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。