Allosteric Modulation in Nicotinic Acetylcholine Receptors

Grinnell College, Grinnell IA

Investigators

Abstract

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.