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

K. T. LePage, J. E. Ishmael, C. M. Low, S. F. Traynelis, Thomas F. Murray

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1-16
Number of pages16
JournalNeuropharmacology
Volume49
Issue number1
DOIs
StatePublished - Jul 2005
Externally publishedYes

Fingerprint

Dextrorphan
Dizocilpine Maleate
N-Methyl-D-Aspartate Receptors
Glycine
Glutamic Acid
Dextromethorphan
Phencyclidine
Ketamine
Ion Channels
Opioid Analgesics
Binding Sites
Mutation

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

Cite this

Differential binding properties of [3H]dextrorphan and [ 3H]MK-801 in heterologously expressed NMDA receptors. / LePage, K. T.; Ishmael, J. E.; Low, C. M.; Traynelis, S. F.; Murray, Thomas F.

In: Neuropharmacology, Vol. 49, No. 1, 07.2005, p. 1-16.

Research output: Contribution to journalArticle

LePage, K. T. ; Ishmael, J. E. ; Low, C. M. ; Traynelis, S. F. ; Murray, Thomas F. / Differential binding properties of [3H]dextrorphan and [ 3H]MK-801 in heterologously expressed NMDA receptors. In: Neuropharmacology. 2005 ; Vol. 49, No. 1. pp. 1-16.
@article{279ad3b6489042eb97d50a9e3aa69167,
title = "Differential binding properties of [3H]dextrorphan and [ 3H]MK-801 in heterologously expressed NMDA receptors",
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.",
author = "LePage, {K. T.} and Ishmael, {J. E.} and Low, {C. M.} and Traynelis, {S. F.} and Murray, {Thomas F.}",
year = "2005",
month = "7",
doi = "10.1016/j.neuropharm.2005.01.029",
language = "English",
volume = "49",
pages = "1--16",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Limited",
number = "1",

}

TY - JOUR

T1 - Differential binding properties of [3H]dextrorphan and [ 3H]MK-801 in heterologously expressed NMDA receptors

AU - LePage, K. T.

AU - Ishmael, J. E.

AU - Low, C. M.

AU - Traynelis, S. F.

AU - Murray, Thomas F.

PY - 2005/7

Y1 - 2005/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=21344449723&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=21344449723&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2005.01.029

DO - 10.1016/j.neuropharm.2005.01.029

M3 - Article

VL - 49

SP - 1

EP - 16

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

IS - 1

ER -