Mechanism of partial agonism at NMDA receptors for a conformationally restricted glutamate analog

Kevin Erreger, Matthew T. Geballe, Shashank M. Dravid, James P. Snyder, David J.A. Wyllie, Stephen F. Traynelis

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

The NMDA ionotropic glutamate receptor is ubiquitous in mammalian central neurons. Because partial agonists bind to the same site as glutamate but induce less channel activation, these compounds provide an opportunity to probe the mechanism of activation of NMDA-type glutamate receptors. Molecular dynamics simulations and site-directed mutagenesis demonstrate that the partial agonist homoquinolinate interacts differently with binding pocket residues than glutamate. Homoquinolinate and glutamate induce distinct changes in the binding pocket, and the binding pocket exhibits significantly more motion with homoquinolinate bound than with glutamate. Patch-clamp recording demonstrates that single-channel activity induced by glutamate or by homoquinolinate has identical single-channel current amplitude and mean open-channel duration but that homoquinolinate slows activation of channel opening relative to glutamate. We hypothesize that agonist-induced conformational changes in the binding pocket control the efficacy of a subunit-specific activation step that precedes the concerted global change in the receptor-channel complex associated with ion channel opening.

Original languageEnglish (US)
Pages (from-to)7858-7866
Number of pages9
JournalJournal of Neuroscience
Volume25
Issue number34
DOIs
StatePublished - Aug 24 2005

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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