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The Journal of Neuroscience, August 24, 2005, 25(34):7858-7866; doi:10.1523/JNEUROSCI.1613-05.2005

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Cellular/Molecular
Mechanism of Partial Agonism at NMDA Receptors for a Conformationally Restricted Glutamate Analog

Kevin Erreger,¹ Matthew T. Geballe,² Shashank M. Dravid,¹ James P. Snyder,² David J. A. Wyllie,³ and Stephen F. Traynelis¹

¹Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, and ²Department of Chemistry, Emory University, Atlanta, Georgia 30322, and ³Division of Neuroscience, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom

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.

Key words: ion channel; glutamate; NMDA; molecular dynamics; structure; gating

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Received April 24, 2005; revised July 18, 2005; accepted July 18, 2005.

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