Abstract
N-methyl-d-aspartate (NMDA) receptors are glutamate-gated ion channels whose function is critical for normal excitatory synaptic transmission in the brain and whose dysfunction has been implicated in several neurologic conditions. NMDA receptor function is subject to extensive allosteric regulation both by endogenous compounds and by exogenous small molecules. Elucidating the structural determinants and mechanism of action by which allosteric regulators control gating will enhance our understanding of NMDA receptor activation and facilitate the development of novel therapeutics. Here, we investigated the structural determinants for (3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (CIQ), a GluN2C/2D-selective positive allosteric modulator. We show that CIQ does not bind to the amino-terminal domain of the NMDA receptor and does not share structural determinants with modulators acting at the agonist-binding domain dimer interface or ion channel pore. Rather, we identified critical determinants of CIQ modulation in the region near the first transmembrane helix of GluN2D, including in a putative pre-M1 cuff helix that may influence channel gating. We also show that mutations within the GluN2D pre-M1 region alter open probability of the NMDA receptor. These results suggest a novel site of action for potentiation of NMDA receptors by small molecules and implicate the pre-M1 region in NMDA receptor gating.
Footnotes
- Received January 26, 2013.
- Accepted March 1, 2013.
This study was supported by the Michael J. Fox Foundation; the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants R01-NS036654, R01-NS065371, and F31-NS071802]; the National Institutes of Health National Institute of General Medical Sciences [Grant T32-GM008602]; and the National Institutes of Health National Institute on Drug Abuse [Grant T32-DA01504006]; as well as by research grants to Emory University from Pfizer Inc. and Lundbeck AS. S.T. is a co-inventor of Emory-owned intellectual property, has an equity position in NeurOp Inc., and is a paid consultant of NeurOp Inc., which is developing NMDA receptor allosteric modulators.
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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