Neuronal nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that mediate fast synaptic transmission and are important and novel therapeutic targets in neurodegenerative diseases and mental illness. Currently there is no atomic-resolution structure for any nicotinic receptor, and no receptor in this Cys-loop receptor superfamily has been structurally characterized in more than one conformation. The long-term objectives of the research are to better understand the conformational changes that underlie the transitions between different functional states and to develop reliable, atomic-resolution models of nAChRs relevant to structure-guided drug design. Toward these goals the following approach will be used. 1. Through receptor ortholog screening, identify an ?7 receptor candidate for crystallization, and test conditions to optimize receptor stability in detergent. 2. Using fast-perfusion patch clamp and single channel analysis, test combinations of construct modifications and pharmacological probes to stabilize distinct receptor conformations. 3. Crystallize receptor in different conformational states and determine atomic-resolution structures of (a) a closed-resting receptor, (b) an open-activated receptor and (c) a closed-desensitized receptor. The structural studies will be complemented with functional assays that test new structure-based hypotheses regarding mechanisms of state transitions in the receptor. The results will have broad implications for the Cys-loop receptor family in general and ?7 nAChRs specifically.

Public Health Relevance

to public health: The proposed studies will provide the first reliable structural templates for design of highly selective and innovative therapeutics useful in Alzheimer's and Parkinson's diseases and schizophrenia. Moreover, an understanding of how the structure of this important class of proteins changes upon activation will lend insight into biophysical process of great importance in addiction and other human nervous system health issues.

Agency
National Institute of Health (NIH)
Type
Research Transition Award (R00)
Project #
5R00NS077983-04
Application #
8708228
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Stewart, Randall R
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390