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Author Notes:

Corresponding author: Tel.: +1 706 542 3014; fax: +1 706 542 3015. E-mail address: klepage@uga.edu (K.T. LePage)

The authors wish to thank Roxanne Armstrong and Kelly Cumuze for excellent technical assistance and Dr. Mark Leid for valuable discussions.

Special thanks to Dr. Jeremy Glasner for assistance in the sequencing of constructs used in this investigation.

Subjects:

Research Funding:

Supported by National Institute on Drug Abuse grant (DA07218) to T.F.M., an F32 National Research Service Award (DA05728) to J.E.I., and NINDS grant (NS36654) to S.F.T.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Pharmacology & Pharmacy
  • Neurosciences & Neurology
  • NEUROSCIENCES
  • PHARMACOLOGY & PHARMACY
  • NMDA receptor
  • dextrorphan
  • MK-801
  • glutamate
  • binding
  • mutagenesis
  • D-ASPARTATE RECEPTOR
  • STRUCTURAL DETERMINANTS
  • EXTRACELLULAR VESTIBULE
  • MOLECULAR DETERMINANTS
  • SUBSTITUTED CYSTEINES
  • CHANNEL BLOCKERS
  • RAT-BRAIN
  • SITE
  • GLUTAMATE
  • PHENCYCLIDINE

Differential binding properties of [H-3]dextrorphan and [H-3]MK-801 in heterologously expressed NMDA receptors

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Journal Title:

Neuropharmacology

Volume:

Volume 49, Number 1

Publisher:

, Pages 1-16

Type of Work:

Article | Post-print: After Peer Review

Abstract:

The N-methyl-D-aspartate receptor (NMDAR) antagonists: MK-801, phencyclidine and ketamine are open-channel blockers with limited clinical value due to psychotomimetic effects. Similarly, the psychotomimetic effects of the dextrorotatory opioids, dextromethorphan and its metabolite dextrorphan, derive from their NMDAR antagonist actions. Differences in the use dependency of blockade, however, suggest that the binding sites for MK-801 and dextrorphan are distinct. In the absence of exogenous glutamate and glycine, the rate of association of [3H]MK-801 with wild-type NR1-1a/NR2A receptors was considerably slower than that for [3H]dextrorphan. Glutamate individually, and in the presence of the co-agonist glycine, had substantial effects on the specific binding of [3H]MK-801, while the binding of [3H]dextrorphan was not affected. Mutation of residues N616 and A627 in the NR1 subunit had a profound effect on [3H]MK-801 binding affinity, while that of [3H]dextrorphan was unaltered. In contrast, NR1 residues, W611 and N812, were critical for specific binding of [ 3H]dextrorphan to NR1-1a/NR2A complexes with no corresponding influence on that of [3H]MK-801. Thus, [3H]dextrorphan and [3H]MK-801 have distinct molecular determinants for high-affinity binding. The ability of [3H]dextrorphan to bind to a closed channel, moreover, indicates that its recognition site is shallower in the ion channel domain than that of MK-801 and may be associated with the extracellular vestibule of the NMDAR. © 2005 Elsevier Ltd. All rights reserved.

Copyright information:

© 2005 Elsevier Ltd.

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