The present work will provide new insights into how drugs bind to and activate a family of receptors that are found throughout the central and peripheral nervous systems. These receptors are called Cys-loop receptors, and they are established therapeutic targets for Alzheimer's disease, schizophrenia, Parkinson's disease, pain, epilepsy, ADHD, autism, depression, addiction and more. Using powerful methodologies developed in previous years of the grant, the structures of the receptors can be modified in precise and subtle ways. In particular, the amino acids that are the building blocks of these protein receptors can be specifically replaced with designed, unnatural amino acids. This allows unprecedented control over the functionality present. How these modifications impact the effectiveness of drugs that target the receptor provides key insights into the mechanism of drug action. A key issue to be addressed will be receptor selectivity - how certain drugs are able to target only specific members of a collection of very closely related receptors. The knowledge generated from these studies will be very valuable to efforts to develop new pharmaceuticals to address the many neurological disorders associated with malfunctions of the Cys-loop receptors.

Public Health Relevance

Neurological disorders, including unipolar depressive disorders, bipolar affective disorder, and schizophrenia, present the greatest health hazard to adults in developed countries, according to the World Health Organization Global Burden of Disease assessment. The present work will provide new insights into how drugs bind to and activate a family of receptors found throughout the central and peripheral nervous systems. Malfunctions of these receptors are associated with the full spectrum of neurological disorders, and knowledge generated by this grant will be of great value to efforts to develop new pharmaceuticals to combat these dreaded diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034407-19
Application #
8606660
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Stewart, Randall R
Project Start
1995-07-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
19
Fiscal Year
2014
Total Cost
$753,948
Indirect Cost
$238,857
Name
California Institute of Technology
Department
Chemistry
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Miles, Timothy F; Lester, Henry A; Dougherty, Dennis A (2015) Allosteric activation of the 5-HT3AB receptor by mCPBG. Neuropharmacology 91:103-8
Dougherty, Dennis A; Van Arnam, Ethan B (2014) In vivo incorporation of non-canonical amino acids by using the chemical aminoacylation strategy: a broadly applicable mechanistic tool. Chembiochem 15:1710-20
Daeffler, Kristina N-M; Lester, Henry A; Dougherty, Dennis A (2014) Functional evaluation of key interactions evident in the structure of the eukaryotic Cys-loop receptor GluCl. ACS Chem Biol 9:2283-90
Nichols, Weston A; Henderson, Brandon J; Yu, Caroline et al. (2014) Lynx1 shifts ?4?2 nicotinic receptor subunit stoichiometry by affecting assembly in the endoplasmic reticulum. J Biol Chem 289:31423-32
Limapichat, Walrati; Dougherty, Dennis A; Lester, Henry A (2014) Subtype-specific mechanisms for functional interaction between ?6?4* nicotinic acetylcholine receptors and P2X receptors. Mol Pharmacol 86:263-74
Marotta, Christopher B; Rreza, Iva; Lester, Henry A et al. (2014) Selective ligand behaviors provide new insights into agonist activation of nicotinic acetylcholine receptors. ACS Chem Biol 9:1153-9
Shih, Pei-Yu; Engle, Staci E; Oh, Gyeon et al. (2014) Differential expression and function of nicotinic acetylcholine receptors in subdivisions of medial habenula. J Neurosci 34:9789-802
Marotta, Christopher B; Dilworth, Crystal N; Lester, Henry A et al. (2014) Probing the non-canonical interface for agonist interaction with an *5 containing nicotinic acetylcholine receptor. Neuropharmacology 77:342-9
Henderson, Brandon J; Srinivasan, Rahul; Nichols, Weston A et al. (2014) Nicotine exploits a COPI-mediated process for chaperone-mediated up-regulation of its receptors. J Gen Physiol 143:51-66
Frazier, Shawnalea J; Cohen, Bruce N; Lester, Henry A (2013) An engineered glutamate-gated chloride (GluCl) channel for sensitive, consistent neuronal silencing by ivermectin. J Biol Chem 288:21029-42

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