Structural and Single-Channel Results Indicate That the Rates of Ligand Binding Domain Closing and Opening Directly Impact AMPA Receptor Gating
Open Access
- 23 January 2008
- journal article
- research article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 28 (4), 932-943
- https://doi.org/10.1523/jneurosci.3309-07.2008
Abstract
At most excitatory central synapses, glutamate is released from presynaptic terminals and binds to postsynaptic AMPA receptors, initiating a series of conformational changes that result in ion channel opening. Efficient transmission at these synapses requires that glutamate binding to AMPA receptors results in rapid and near-synchronous opening of postsynaptic receptor channels. In addition, if the information encoded in the frequency of action potential discharge is to be transmitted faithfully, glutamate must dissociate from the receptor quickly, enabling the synapse to discriminate presynaptic action potentials that are spaced closely in time.The current view is that the efficacy of agonists is directly related to the extent to which ligand binding results in closure of the binding domain. For glutamate to dissociate from the receptor, however, the binding domain must open. Previously, we showed that mutations in glutamate receptor subunit 2 that should destabilize the closed conformation not only sped deactivation but also altered the relative efficacy of glutamate and quisqualate. Here we present x-ray crystallographic and single-channel data that support the conclusions that binding domain closing necessarily precedes channel opening and that the kinetics of conformational changes at the level of the binding domain importantly influence ion channel gating. Our findings suggest that the stability of the closed-cleft conformation has been tuned during evolution so that glutamate dissociates from the receptor as rapidly as possible but remains an efficacious agonist.This publication has 44 references indexed in Scilit:
- Structural aspects of AMPA receptor activation, desensitization and deactivationCurrent Opinion in Neurobiology, 2007
- Single‐channel study of the spasmodic mutation α1A52S in recombinant rat glycine receptorsJournal Of Physiology-London, 2007
- A stepwise mechanism for acetylcholine receptor channel gatingNature, 2007
- The Relationship between Agonist Potency and AMPA Receptor KineticsBiophysical Journal, 2006
- Mechanism of Partial Agonism at NMDA Receptors for a Conformationally Restricted Glutamate AnalogJournal of Neuroscience, 2005
- Single-Channel Behavior of Heteromeric α1β Glycine Receptors: An Attempt to Detect a Conformational Change before the Channel OpensJournal of Neuroscience, 2004
- Reaction mechanism determines NMDA receptor response to repetitive stimulationNature, 2004
- Mechanism of Activation and Selectivity in a Ligand-Gated Ion Channel: Structural and Functional Studies of GluR2 and Quisqualate,Biochemistry, 2002
- Mechanism of glutamate receptor desensitizationNature, 2002
- Satisfying Hydrogen Bonding Potential in ProteinsJournal of Molecular Biology, 1994