GluN1 | Ionotropic glutamate receptors | IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

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GluN1

Target id: 455

Nomenclature: GluN1

Family: Ionotropic glutamate receptors

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 3 1 938 9q34.3 GRIN1 glutamate ionotropic receptor NMDA type subunit 1
Mouse 3 1 938 2 A3 Grin1 glutamate receptor, ionotropic, NMDA1 (zeta 1)
Rat 3 1 938 3p13 Grin1 glutamate ionotropic receptor NMDA type subunit 1
Previous and Unofficial Names
NMDAR1 | GluRzeta1 | NMDA-R1 | glutamate receptor, ionotropic, NMDA1 (zeta 1) | glutamate receptor
Database Links
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of GluN1a/GluN2B NMDA Receptor Ion Channel
PDB Id:  4PE5
Resolution:  3.96Å
Species:  Rat
References:  5
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of amino terminal domains of the NMDA receptor subunit GluN1 and GluN2B in complex with ifenprodil
PDB Id:  3QEL
Ligand:  ifenprodil
Resolution:  2.6Å
Species:  Rat
References:  6
Natural/Endogenous Ligands
D-aspartic acid
D-serine
glycine
L-aspartic acid
L-glutamic acid

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
glycine Hs Agonist - -
[Binds to: glycine site]
L-aspartic acid Hs Agonist - -
[Binds to: glutamate site]
(+)-HA966 Hs Partial agonist - -
[Binds to: glycine site]
(RS)-(tetrazol-5-yl)glycine Hs Full agonist - -
[Binds to: glutamate site]
[3H]glycine Hs Full agonist - -
[Binds to: glycine site]
D-serine Hs Agonist - -
[Binds to: glycine site]
homoquinolinic acid Hs Partial agonist - -
[Binds to: glutamate site]
NMDA Hs Full agonist - -
[Binds to: glutamate site]
D-aspartic acid Hs Agonist - -
[Binds to: glutamate site]
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]MDL105519 Rn Antagonist ~8.5 pKd 1
pKd ~8.5 (Kd ~3x10-9 M) [Binds to: glycine site] [1]
GV196771A Rn Antagonist 8.1 – 8.4 pKi 2
pKi 8.1 – 8.4 (Ki 8x10-9 – 4x10-9 M) [Binds to: glycine site] [2]
Description: Measuring the high affinity binding site for the compound at two different splice variants expressed in HEK293 cells.
compound 8 [PMID: 17562362} Hs Antagonist 9.0 pIC50 3
pIC50 9.0 (IC50 1x10-9 M) [3]
L701324 Rn Antagonist 8.7 pIC50 9
pIC50 8.7 (IC50 2x10-9 M) [Binds to: glycine site] [9]
Description: Measuring inhibition of [3H]L-689,560 binding to the strychnine-insensitive glycine site on rat brain membranes.
L689560 Rn Antagonist 8.1 pIC50 10
pIC50 8.1 (IC50 7.4x10-9 M) [Binds to: glycine site] [10]
Description: Measuring displacement of [3H]glycine from rat brain membranes
5,7-dichlorokynurenic acid Hs Antagonist - -
[Binds to: glycine site]
[3H]CGP39653 Hs Antagonist - -
[Binds to: glutamate site]
[3H]CGP61594 Hs Antagonist - -
[Binds to: glycine site] photoaffinity ligand
[3H]CGS19755 Hs Antagonist - -
[Binds to: glutamate site]
[3H]CPP Hs Antagonist - -
[Binds to: glutamate site]
[3H]L689560 Hs Antagonist - -
[Binds to: glycine site]
[3H]dizocilpine Hs Antagonist - -
[Binds to: cation channel]
View species-specific antagonist tables
Antagonist Comments
GV196771A has two binding sites on rat GluN1 subunits expressed in HEK293 cells. The low affinity site has a Ki value of 121-153nM depending on the slice variant tested [2].
Immunopharmacology Comments
Autoantibodies that target GluN1 cause anti-NMDA receptor encephalitis [8,11,14]. Approximately 50% of cases occur in the presence ovarian teratoma. The condition can manifest postviral infection [12], but many cases are idiopathic [7]. Anti-NMDA receptor encephalitis has been identified in a non-human mammal [13], and fulminant disease can be induced in a mouse model by active immunisation with conformationally stabilised, native-like NMDA holoreceptors (GluN1-GluN2B tetramers embedded in liposomes) [4].
Clinically-Relevant Mutations and Pathophysiology
Disease:  Mental retardation, autosomal dominant 8; MRD8
Synonyms: Autosomal dominant non-syndromic intellectual disability [Orphanet: ORPHA178469] [Disease Ontology: DOID:0060307]
Disease Ontology: DOID:0060307
OMIM: 614254
Orphanet: ORPHA178469

References

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1. Chazot PL, Reiss C, Chopra B, Stephenson FA. (1998) [3H]MDL 105,519 binds with equal high affinity to both assembled and unassembled NR1 subunits of the NMDA receptor. Eur. J. Pharmacol., 353 (1): 137-40. [PMID:9721050]

2. Chopra B, Chazot PL, Stephenson FA. (2000) Characterization of the binding of two novel glycine site antagonists to cloned NMDA receptors: evidence for two pharmacological classes of antagonists. Br. J. Pharmacol., 130 (1): 65-72. [PMID:10780999]

3. Deur C, Agrawal AK, Baum H, Booth J, Bove S, Brieland J, Bunker A, Connolly C, Cornicelli J, Dumin J et al.. (2007) N-(6,7-dichloro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-N-alkylsulfonamides as peripherally restricted N-methyl-D-aspartate receptor antagonists for the treatment of pain. Bioorg. Med. Chem. Lett., 17 (16): 4599-603. [PMID:17562362]

4. Jones BE, Tovar KR, Goehring A, Jalali-Yazdi F, Okada NJ, Gouaux E, Westbrook GL. (2019) Autoimmune receptor encephalitis in mice induced by active immunization with conformationally stabilized holoreceptors. Sci Transl Med, 11 (500). DOI: 10.1126/scitranslmed.aaw0044 [PMID:31292262]

5. Karakas E, Furukawa H. (2014) Crystal structure of a heterotetrameric NMDA receptor ion channel. Science, 344 (6187): 992-7. [PMID:24876489]

6. Karakas E, Simorowski N, Furukawa H. (2011) Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors. Nature, 475 (7355): 249-53. [PMID:21677647]

7. Kayser MS, Dalmau J. (2016) Anti-NMDA receptor encephalitis, autoimmunity, and psychosis. Schizophr. Res., 176 (1): 36-40. [PMID:25458857]

8. Kelleher E, Barry H, Cotter DR, Corvin A, Murphy KC. (2019) Autoantibodies and Psychosis. Curr Top Behav Neurosci, [Epub ahead of print]. [PMID:31292938]

9. Kulagowski JJ, Baker R, Curtis NR, Leeson PD, Mawer IM, Moseley AM, Ridgill MP, Rowley M, Stansfield I, Foster AC et al.. (1994) 3'-(Arylmethyl)- and 3'-(aryloxy)-3-phenyl-4-hydroxyquinolin-2(1H)-ones: orally active antagonists of the glycine site on the NMDA receptor. J. Med. Chem., 37 (10): 1402-5. [PMID:8182696]

10. Leeson PD, Carling RW, Moore KW, Moseley AM, Smith JD, Stevenson G, Chan T, Baker R, Foster AC, Grimwood S et al.. (1992) 4-Amido-2-carboxytetrahydroquinolines. Structure-activity relationships for antagonism at the glycine site of the NMDA receptor. J. Med. Chem., 35 (11): 1954-68. [PMID:1534584]

11. Newman MP, Blum S, Wong RC, Scott JG, Prain K, Wilson RJ, Gillis D. (2016) Autoimmune encephalitis. Intern Med J, 46 (2): 148-57. [PMID:26899887]

12. Prüss H. (2017) Postviral autoimmune encephalitis: manifestations in children and adults. Curr. Opin. Neurol., 30 (3): 327-333. [PMID:28234798]

13. Prüss H, Leubner J, Wenke NK, Czirják GÁ, Szentiks CA, Greenwood AD. (2015) Anti-NMDA Receptor Encephalitis in the Polar Bear (Ursus maritimus) Knut. Sci Rep, 5: 12805. [PMID:26313569]

14. Venkatesan A, Adatia K. (2017) Anti-NMDA-Receptor Encephalitis: From Bench to Clinic. ACS Chem Neurosci, 8 (12): 2586-2595. [PMID:29077387]

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