Reduced glutamatergic signaling is a final common denominator of a number of disorders that reduce cognitive ability, including mild cognitive impairment, Alzheimer's disease, schizophrenia, ADHD, narcolepsy, autism, depression, schizophrenia and Parkinson's disease. These neurological and psychiatric disorders affect millions of people in this country and hundreds of millions across world populations. Many of these diseases are progressive and are currently incurable. The best hope for improving the quality of life of afflicted individuals may lie with mitigating the most debilitating symptoms, and certainly cognitive decline significantly impacts both the quality of life and the ability to contribute to the workforce. AMPA receptor modulators show promise in the treatment of diseases resulting in the loss of cognitive function. There are multiple classes of positive allosteric modulators that act through a common binding site to shape AMPA receptor deactivation and desensitization. The long-term goal of these studies is to study the mechanism of receptor deactivation and desensitization, and how drugs and proteins that modulate these processes exert their actions. The following specific objectives will utilize molecular and structural biology, patch clamp electrophysiology, fluorescence energy transfer, a new methodology of probing tertiary and quaternary protein complexes using metabolic biotinylation, and computational modeling: 1. To determine the efficacy of modulation of deactivation and desensitization of AMPA receptor mutations that intrinsically perturb deactivation and desensitization, using each of the three classes of modulator, in the absence or presence of the AMPA receptor accessory protein, stargazin. 2. To determine how modulation by stargazin is similar to or differs from modulation of deactivation and/or desensitization by these compounds. A biophysical approach to study modulation of deactivation and desensitization using drugs that have intrinsically different modes of action may better direct future efforts to design AMPA-selective, cognition-enhancing drugs.

Public Health Relevance

Reduced glutamatergic signaling is a final common denominator of a number of disorders that reduce cognitive ability, including mild cognitive impairment, Alzheimer's disease, schizophrenia, ADHD, narcolepsy, autism, depression, schizophrenia and Parkinson's disease. AMPA receptor modulators show promise in the treatment of diseases resulting in the loss of cognitive function. A biophysical approach to study modulation of deactivation and desensitization using drugs that have intrinsically different modes of action may better direct future efforts to design AMPA-selective, cognition-enhancing drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH064700-09
Application #
8210962
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Nadler, Laurie S
Project Start
2001-09-21
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
9
Fiscal Year
2012
Total Cost
$327,443
Indirect Cost
$104,693
Name
Colorado State University-Fort Collins
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Partin, Kathryn M (2015) AMPA receptor potentiators: from drug design to cognitive enhancement. Curr Opin Pharmacol 20:46-53
Weeks, Autumn M; Harms, Jonathan E; Partin, Kathryn M et al. (2014) Functional insight into development of positive allosteric modulators of AMPA receptors. Neuropharmacology 85:57-66
Harms, Jonathan E; Benveniste, Morris; Kessler, Markus et al. (2014) A charge-inverting mutation in the "linker" region of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors alters agonist binding and gating kinetics independently of allosteric modulators. J Biol Chem 289:10702-14
Harms, Jonathan E; Benveniste, Morris; Maclean, John K F et al. (2013) Functional analysis of a novel positive allosteric modulator of AMPA receptors derived from a structure-based drug design strategy. Neuropharmacology 64:45-52
Timm, David E; Benveniste, Morris; Weeks, Autumn M et al. (2011) Structural and functional analysis of two new positive allosteric modulators of GluA2 desensitization and deactivation. Mol Pharmacol 80:267-80
Bedoukian, Matthew A; Weeks, Autumn M; Partin, Kathryn M (2006) Different domains of the AMPA receptor direct stargazin-mediated trafficking and stargazin-mediated modulation of kinetics. J Biol Chem 281:23908-21
Leever, J Duncan; Clark, Suzanne; Weeks, Autumn M et al. (2003) Identification of a site in GluR1 and GluR2 that is important for modulation of deactivation and desensitization. Mol Pharmacol 64:5-10