3D Structure and mechanism of the alpha7 nicotinic acetylcholine receptor

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 DESCRIPTION (provided by applicant): 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 α7 nicotinic receptor subtype. The α7 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 α7 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 α7 receptor in different conformational states. Comparison of the α7 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 α7 compounds selective for different receptor states.