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A High-content Assay for Monitoring AMPA Receptor Trafficking
Published on: January 28, 2019
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Homomeric GluA2(R) AMPA receptors can conduct when desensitized
Ian D Coombs1, David Soto1,2, Thomas P McGee1
1Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
Nature Communications
|September 22, 2019
Summary
AMPA receptors (AMPARs) typically close when desensitized. However, this study shows homomeric Q/R-edited AMPARs remain open, allowing ion flow in a desensitized state, challenging previous assumptions.
Area of Science:
- Neuroscience
- Molecular Biology
- Biophysics
Background:
- Ligand-gated ion channels, including AMPA-type glutamate receptors (AMPARs), exhibit desensitization, a decline in current during sustained agonist exposure.
- Recent structural studies (cryo-EM) suggest AMPARs are closed in the desensitized state.
Purpose of the Study:
- To investigate whether AMPARs allow ion flow in the desensitized state.
- To characterize the functional properties of homomeric Q/R-edited AMPARs in desensitization.
- To probe the conformation of the desensitized ligand-binding domain.
Main Methods:
- Electrophysiology (fluctuation analysis, single-channel recording)
- Kinetic modeling
- Crystallography of cross-linked cysteine mutants
Main Results:
- Homomeric Q/R-edited AMPARs (GluA2(R)) exhibit significant steady-state currents when desensitized.
- Anomalous current-variance relationships were observed.
- Evidence suggests steady-state currents are primarily conducted by desensitized receptors.
Conclusions:
- Desensitized homomeric Q/R-edited AMPARs remain ion-conducting, contradicting the closed-channel model.
- This functional readout provides insights into the conformation of the desensitized ligand-binding domain.
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