We study allosteric modulation of neuronal nicotinic acetylcholine receptors (nAChRs). These ligand-gated ion channels are the seat of nicotine addiction and are implicated in a wide range of other neurological disorders. Allosteric modulation of nAChRs is growing in importance as it becomes better understood and as novel compounds with this pharmacological profile are identified. The binding sites for a class of model modulatory compounds, quite specific for one subtype of neuronal nAChR, are known, and some molecular determinants of transducing modulator binding information into channel activity have been identified. Building on this previous work, we now propose to further refine our understanding of the movement of one sub- structure involved in intra-molecular signal transduction and of the molecular determinants of modulator site specificity. In addition, questions about channel gating efficacy will be addressed in terms of the optimal number and arrangement of modulator sites relative to agonist sites and the role of hydrophobic residues in the extracellular domain core. These studies will employ pharmacological characterization of expressed receptors with point mutations or concatenated subunits by macroscopic voltage-clamp recordings, as well as chemical modification analyses. The project also includes a targeted structure-activity relationship study with new modulator analogues. In some cases, to support these primary aims, we will explore the modulation mechanisms further by single-channel recordings. Our work is innovative because we are challenging the paradigm of activation of nAChRs by occupying two agonist binding sites. We are studying a recently identified nAChR ligand binding site, and the work we propose stands to substantially strengthen the foundation for rational design of nAChR allosteric modulators, a drug class with possible clinical applications.

Public Health Relevance

We study neuronal nicotinic acetylcholine receptors, a family of proteins that mediate nicotine addiction and are implicated in various other neurological disorders, such as Alzheimer's and Parkinson's diseases. We propose experiments to examine how these proteins move when they are active, a property fundamental to their function, and how certain drugs enhance their activity. The long-range impact of this work is improved therapeutic approaches to nicotine addiction and other neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
3R15NS090368-01S1
Application #
9057347
Study Section
Program Officer
Silberberg, Shai D
Project Start
2014-09-30
Project End
2017-09-29
Budget Start
2015-09-30
Budget End
2017-09-29
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Grinnell College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
062763016
City
Grinnell
State
IA
Country
United States
Zip Code
50112