Neuronal nicotinic acetylcholine receptors (nAChRs) are essential therapeutic targets for mental health and neurodegenerative disorders. These pentameric ligand-gated ion channels are members of the Cys-loop receptor superfamily, which mediate fast neurotransmission throughout the central and peripheral nervous systems.
We aim to elucidate general principles underlying Cys-loop receptor function. From a biophysical perspective, we want to understand modes of binding and modulation by pharmacological agents, conformational changes underlying state transitions, and mechanisms of ion permeation and selectivity in the nAChR and broader Cys-loop receptor family. Progress toward each of these goals is directly linked to a better understanding of basic mechanisms of nervous system disorders and the design of therapeutics to treat them. Here we propose to structurally characterize the homopentameric ?7 nicotinic receptor subtype. The ?7 subtype is a novel target in treating schizophrenia, Alzheimer's and Parkinson's diseases. Like most ligand- gated channels, in the continued presence of agonist the ?7 receptor quickly desensitizes. Once ligand dissociates, the receptor will return to the resting state. The goal of the work proposed here is to determine high resolution structures of the ?7 receptor in different conformational states. Comparison of the ?7 structures in its three principal functional states will allow, for te first time, a structural view of the gating cycle from resting to activated to desensitized. The structural studies will be complemented with pharmacology and electrophysiology to test mechanistic hypotheses that arise from the structures. Our proposed studies will lead to a better understanding of the mechanisms of receptor function and will provide a molecular blueprint for design of ?7 compounds selective for different receptor states.
The proposed studies will elucidate how the structure of this important class of proteins changes upon activation and desensitization, which will lend insight into biophysical process of great importance in normal nervous system physiology and in disease states. Moreover, this research project will provide structural templates for design of highly selective and innovative therapeutics useful in Alzheimer's and Parkinson's diseases and schizophrenia.
|Walsh Jr, Richard M; Roh, Soung-Hun; Gharpure, Anant et al. (2018) Structural principles of distinct assemblies of the human ?4?2 nicotinic receptor. Nature 557:261-265|
|Zhu, Shaotong; Noviello, Colleen M; Teng, Jinfeng et al. (2018) Structure of a human synaptic GABAA receptor. Nature 559:67-72|