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Title: Mechanism of Positive Allosteric Modulators Acting on AMPA Receptors

Abstract

Ligand-gated ion channels involved in the modulation of synaptic strength are the AMPA, kainate, and NMDA glutamate receptors. Small molecules that potentiate AMPA receptor currents relieve cognitive deficits caused by neurodegenerative diseases such as Alzheimer's disease and show promise in the treatment of depression. Previously, there has been limited understanding of the molecular mechanism of action for AMPA receptor potentiators. Here we present cocrystal structures of the glutamate receptor GluR2 S1S2 ligand-binding domain in complex with aniracetam [1-(4-methoxybenzoyl)-2-pyrrolidinone] or CX614 (pyrrolidino-1, 3-oxazino benzo-1, 4-dioxan-10-one), two AMPA receptor potentiators that preferentially slow AMPA receptor deactivation. Both potentiators bind within the dimer interface of the nondesensitized receptor at a common site located on the twofold axis of molecular symmetry. Importantly, the potentiator binding site is adjacent to the 'hinge' in the ligand-binding core 'clamshell' that undergoes conformational rearrangement after glutamate binding. Using rapid solution exchange, patch-clamp electrophysiology experiments, we show that point mutations of residues that interact with potentiators in the cocrystal disrupt potentiator function. We suggest that the potentiators slow deactivation by stabilizing the clamshell in its closed-cleft, glutamate-bound conformation.

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
913701
Report Number(s):
BNL-78269-2007-JA
Journal ID: ISSN 0270-6474; JNRSDS; TRN: US200804%%40
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. Neurosci.; Journal Volume: 25
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; RECEPTORS; NERVOUS SYSTEM DISEASES; CRYSTAL STRUCTURE; DEACTIVATION; ELECTROPHYSIOLOGY; GENE MUTATIONS; LIGANDS; MITIGATION; national synchrotron light source

Citation Formats

Jin,R., Clark, S., Weeks, A., Dudman, J., Gouaux, E., and Partin, K. Mechanism of Positive Allosteric Modulators Acting on AMPA Receptors. United States: N. p., 2005. Web. doi:10.1523/JNEUROSCI.2567-05.2005.
Jin,R., Clark, S., Weeks, A., Dudman, J., Gouaux, E., & Partin, K. Mechanism of Positive Allosteric Modulators Acting on AMPA Receptors. United States. doi:10.1523/JNEUROSCI.2567-05.2005.
Jin,R., Clark, S., Weeks, A., Dudman, J., Gouaux, E., and Partin, K. 2005. "Mechanism of Positive Allosteric Modulators Acting on AMPA Receptors". United States. doi:10.1523/JNEUROSCI.2567-05.2005.
@article{osti_913701,
title = {Mechanism of Positive Allosteric Modulators Acting on AMPA Receptors},
author = {Jin,R. and Clark, S. and Weeks, A. and Dudman, J. and Gouaux, E. and Partin, K.},
abstractNote = {Ligand-gated ion channels involved in the modulation of synaptic strength are the AMPA, kainate, and NMDA glutamate receptors. Small molecules that potentiate AMPA receptor currents relieve cognitive deficits caused by neurodegenerative diseases such as Alzheimer's disease and show promise in the treatment of depression. Previously, there has been limited understanding of the molecular mechanism of action for AMPA receptor potentiators. Here we present cocrystal structures of the glutamate receptor GluR2 S1S2 ligand-binding domain in complex with aniracetam [1-(4-methoxybenzoyl)-2-pyrrolidinone] or CX614 (pyrrolidino-1, 3-oxazino benzo-1, 4-dioxan-10-one), two AMPA receptor potentiators that preferentially slow AMPA receptor deactivation. Both potentiators bind within the dimer interface of the nondesensitized receptor at a common site located on the twofold axis of molecular symmetry. Importantly, the potentiator binding site is adjacent to the 'hinge' in the ligand-binding core 'clamshell' that undergoes conformational rearrangement after glutamate binding. Using rapid solution exchange, patch-clamp electrophysiology experiments, we show that point mutations of residues that interact with potentiators in the cocrystal disrupt potentiator function. We suggest that the potentiators slow deactivation by stabilizing the clamshell in its closed-cleft, glutamate-bound conformation.},
doi = {10.1523/JNEUROSCI.2567-05.2005},
journal = {J. Neurosci.},
number = ,
volume = 25,
place = {United States},
year = 2005,
month = 1
}
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