Allosteric Modulation in Nicotinic Acetylcholine Receptors

在化学系生命过程化学项目的支持下，格林内尔学院的Mark Levandoski博士将研究烟碱型乙酰胆碱受体如何对神经递质做出反应，神经递质是控制整个神经系统中细胞相互通信的化学信号。这些受体改变其形状，以控制带电粒子进入肌肉细胞和神经元的通道。这个项目将使用高水平的计算方法来研究乙酰胆碱或尼古丁如何影响这些形状的变化。乙酰胆碱是人体内自然存在的一种神经递质，尼古丁是使用烟草产品产生的。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(科学、技术、工程和数学)领域处于弱势地位的学生接触科学的机会，改善STEM教育，并为更多样化、更全球化的STEM工作做出贡献。尼古丁乙酰胆碱受体在记忆、注意力和运动控制等高级大脑功能中发挥重要作用。这些受体经过了深入的研究，使它们成为一个非常大的配体门控离子通道家族的基础样本。二十年来，莱万多斯基博士的研究一直专注于小分子的作用，这些小分子在不激活系统本身的情况下调节受体状态的转变，这种化合物的作用类似于分子变阻器。该项目将应用分子动力学模拟来阐明受体结合部位的局部结构元素，以及模型变构调节器如何影响将调节器结合转变为通道门控的全球变化。这些模拟的结果将允许对来自PI实验室和其他实验室的大量功能电生理学数据进行分子解释。该项目旨在提供一个全长、异构型尼古丁受体如何与变构调节剂相互作用的全面视角。该项目由生命过程化学计划和既定的刺激竞争研究计划(EPSCoR)联合资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.