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Author Notes:

Corresponding author: Anders S. Kristensen, Dept. of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. Telephone: +45 3533 6505; fax: +45 3533 6040; ask@sund.ku.dk.

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Research Funding:

This work was supported by the GluTarget program of excellence Ph.D. fellowship to M.H.P.from University of Copenhagen and research grants from Aase and Ejnar Danielsen Foundation, Brd. Hartmann Foundation, Carlsberg Foundation, Fonden for Lægemiddelvidenskabens Fremme, Lundbeck Foundation and Direktør Ib Henriksen Foundation.

This work was also supported by NIH-NINDS (NS036654 S.F.T.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • glutamate receptor
  • NMDA receptor
  • channel block
  • mutational analysis
  • electrophysiology
  • D-ASPARTATE RECEPTORS
  • IONOTROPIC GLUTAMATE RECEPTORS
  • VOLTAGE-DEPENDENT BLOCK
  • FUNCTIONAL-CHARACTERIZATION
  • ANTHRAQUINONE POLYAMINES
  • STRUCTURAL DETERMINANTS
  • HIPPOCAMPAL-NEURONS
  • SELECTIVITY FILTER
  • ACTIVATED CHANNELS
  • MAGNESIUM BLOCK

Binding of ArgTX-636 in the NMDA Receptor Ion Channel

Tools:

Journal Title:

Journal of Molecular Biology

Volume:

Volume 427, Number 1

Publisher:

, Pages 176-189

Type of Work:

Article | Post-print: After Peer Review

Abstract:

The N-methyl-d-aspartate receptors (NMDARs) constitute an important class of ligand-gated cation channels that are involved in the majority of excitatory neurotransmission in the human brain. Compounds that bind in the NMDAR ion channel and act as blockers are use- and voltage-dependent inhibitors of NMDAR activity and have therapeutic potential for treatment of a variety of brain diseases or as pharmacological tools for studies of the neurobiological role of NMDARs. We have performed a kinetic analysis of the blocking mechanism of the prototypical polyamine toxin NMDAR ion channel blocker argiotoxin-636 (ArgTX-636) at recombinant GluN1/2A receptors to provide detailed information on the mechanism of block. The predicted binding site of ArgTX-636 is in the pore region of the NMDAR ion channel formed by residues in the transmembrane M3 and the M2 pore-loop segments of the GluN1 and GluN2A subunits. To assess the predicted binding mode in further detail, we performed an alanine- and glycine-scanning mutational analysis of this pore-loop segment to systematically probe the role of pore-lining M2 residues in GluN1 and GluN2A in the channel block by ArgTX-636. Comparison of M2 positions in GluN1 and GluN2A where mutation influences ArgTX-636 potency suggests differential contribution of the M2-loops of GluN1 and GluN2A to binding of ArgTX-636. The results of the mutational analysis are highly relevant for the future structure-based development of argiotoxin-derived NMDAR channel blockers.

Copyright information:

© 2014 Elsevier Ltd. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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