How AMPA receptor desensitization depends on receptor occupancy

Antoine Robert; James R Howe

doi:10.1523/JNEUROSCI.23-03-00847.2003

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How AMPA receptor desensitization depends on receptor occupancy

Journal article

Open access

Peer reviewed

How AMPA receptor desensitization depends on receptor occupancy

Antoine Robert and James R Howe

The Journal of neuroscience, Vol.23(3), pp.847-858

02/01/2003

DOI: 10.1523/JNEUROSCI.23-03-00847.2003

PMCID: PMC6741906

PMID: 12574413

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https://doi.org/10.1523/JNEUROSCI.23-03-00847.2003View

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Abstract

AMPA-type glutamate receptors mediate fast excitatory transmission at many central synapses, and rapid desensitization of these receptors can shape the decay of synaptic currents and limit the fidelity of high-frequency synaptic transmission. Here we use a combination of fast glutamate application protocols and kinetic simulations to determine how AMPA receptor desensitization depends on the number of subunits occupied by glutamate. We show that occupancy of a single subunit is sufficient to desensitize AMPA-type channels and that receptors with one to four glutamates bound enter desensitization at similar rates. We find that recovery from desensitization follows a similar sigmoid time course for channels with two to four glutamates bound but is faster and exponential for singly occupied channels. The results suggest that desensitization, at intermediate and high glutamate concentrations, is accompanied by two conformational changes that slow glutamate dissociation. We propose a kinetic scheme that accurately predicts several types of experimental results and differs significantly from previous models in the assignment of affinities for binding to closed and desensitized states. We conclude that desensitization involves a rearrangement that stabilizes the binding domains of one subunit in each dimer in a partially closed conformation. This stabilization likely results from an interaction at the dimer-dimer interface between the binding domains of adjacent subunits.

Models, Theoretical

Cell Line

Kidney - drug effects

Glutamic Acid - pharmacology

Excitatory Amino Acids - pharmacology

Humans

Protein Conformation - drug effects

Kidney - cytology

Dose-Response Relationship, Drug

Perfusion - methods

Kidney - metabolism

Patch-Clamp Techniques

Transfection

Binding Sites - physiology

Glutamic Acid - pharmacokinetics

Kinetics

Excitatory Amino Acids - pharmacokinetics

Receptors, AMPA - drug effects

Receptors, AMPA - genetics

Receptors, AMPA - metabolism

Details

Title: Subtitle: How AMPA receptor desensitization depends on receptor occupancy
Creators: Antoine Robert - Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA
James R Howe
Resource Type: Journal article
Publication Details: The Journal of neuroscience, Vol.23(3), pp.847-858
Publisher: United States
DOI: 10.1523/JNEUROSCI.23-03-00847.2003
PMID: 12574413
PMCID: PMC6741906
ISSN: 0270-6474
eISSN: 1529-2401
Grant note: GM58926 / NIGMS NIH HHS NS37874 / NINDS NIH HHS
Language: English
Date published: 02/01/2003
Academic Unit: Surgery
Record Identifier: 9984051871702771

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