QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, January 23, 2008, 28(4):932-943; doi:10.1523/JNEUROSCI.3309-07.2008

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Zhang, W. Articles by Howe, J. R. PubMed PubMed Citation Articles by Zhang, W. Articles by Howe, J. R.

 Previous Article  |  Next Article 

Cellular/Molecular
Structural and Single-Channel Results Indicate That the Rates of Ligand Binding Domain Closing and Opening Directly Impact AMPA Receptor Gating

Wei Zhang, ^* Yoonsang Cho, ^* Elias Lolis, and James R. Howe

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066

Correspondence should be addressed to James R. Howe, Department of Pharmacology, Yale University School of Medicine, SHM B-251, 333 Cedar Street, New Haven, CT 06520-8066. Email: james.howe{at}yale.edu

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.

Key words: AMPA receptor; channel; glutamate; glutamate receptor; kinetic [kinetics]; structure

---

Received July 20, 2007; revised Nov. 23, 2007; accepted Nov. 23, 2007.

Correspondence should be addressed to James R. Howe, Department of Pharmacology, Yale University School of Medicine, SHM B-251, 333 Cedar Street, New Haven, CT 06520-8066. Email: james.howe{at}yale.edu

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help