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Positive Modulatory Interactions of NMDA Receptor GluN1/2B Ligand Binding Domains Attenuate Antagonists Activity

Bledsoe, Douglas ; Tamer, Ceyhun ; Mesic, Ivana ; Madry, Christian ; Klein, Bradley G. ; Laube, Bodo ; Costa, Blaise M. (2024)
Positive Modulatory Interactions of NMDA Receptor GluN1/2B Ligand Binding Domains Attenuate Antagonists Activity.
In: Frontiers in Pharmacology, 2017, 8
doi: 10.26083/tuprints-00016216
Article, Secondary publication, Publisher's Version

Copyright Information: CC BY 4.0 International - Creative Commons, Attribution.

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Item Type: Article
Type of entry: Secondary publication
Title: Positive Modulatory Interactions of NMDA Receptor GluN1/2B Ligand Binding Domains Attenuate Antagonists Activity
Language: English
Date: 8 March 2024
Place of Publication: Darmstadt
Year of primary publication: 9 May 2017
Place of primary publication: Lausanne
Publisher: Frontiers Media S.A.
Journal or Publication Title: Frontiers in Pharmacology
Volume of the journal: 8
Collation: 8 Seiten
DOI: 10.26083/tuprints-00016216
Corresponding Links:
Origin: Secondary publication DeepGreen

N-methyl D-aspartate receptors (NMDAR) play crucial role in normal brain function and pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDAR contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that include six different gene products; four GluN2 (A–D) and two GluN3 (A–B) subunits. The heterogeneity of subunit combination facilities the distinct function of NMDARs. All GluN subunits contain an extracellular N-terminal Domain (NTD) and ligand binding domain (LBD), transmembrane domain (TMD) and an intracellular C-terminal domain (CTD). Interaction between the GluN1 and co-assembling GluN2/3 subunits through the LBD has been proven crucial for defining receptor deactivation mechanisms that are unique for each combination of NMDAR. Modulating the LBD interactions has great therapeutic potential. In the present work, by amino acid point mutations and electrophysiology techniques, we have studied the role of LBD interactions in determining the effect of well-characterized pharmacological agents including agonists, competitive antagonists, and allosteric modulators. The results reveal that agonists (glycine and glutamate) potency was altered based on mutant amino acid sidechain chemistry and/or mutation site. Most antagonists inhibited mutant receptors with higher potency; interestingly, clinically used NMDAR channel blocker memantine was about three-fold more potent on mutated receptors (N521A, N521D, and K531A) than wild type receptors. These results provide novel insights on the clinical pharmacology of memantine, which is used for the treatment of mild to moderate Alzheimer's disease. In addition, these findings demonstrate the central role of LBD interactions that can be exploited to develop novel NMDAR based therapeutics.

Uncontrolled Keywords: NMDA receptor, Ligand Binding Domain (LBD), competitive antagonists, memantine, interface
Identification Number: Artikel-ID: 229
Status: Publisher's Version
URN: urn:nbn:de:tuda-tuprints-162162
Additional Information:

This article is part of the Research Topic: Contribution of system biology technologies to disease-modifying drug development for neurodegeneration.

Specialty section: This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology

Classification DDC: ?? ddc_dnb_610 ??
Divisions: ?? fb10_nns ??
Date Deposited: 08 Mar 2024 13:16
Last Modified: 14 May 2024 13:49
SWORD Depositor: Deep Green
URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/16216
PPN: 517098784
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