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GluN1

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Target id: 455

Nomenclature: GluN1

Family: Ionotropic glutamate receptors

Contents:

Gene and Protein Information Click here for help
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 17.14 cM Grin1 glutamate receptor, ionotropic, NMDA1 (zeta 1)
Rat 3 1 938 3p13 Grin1 glutamate ionotropic receptor NMDA type subunit 1
Previous and Unofficial Names Click here for help
NMDAR1 | GluRzeta1 | NMDA-R1 | glutamate receptor, ionotropic, NMDA1 (zeta 1) | glutamate receptor
Database Links Click here for help
Alphafold Q05586 (Hs), P35438 (Mm), P35439 (Rn)
ChEMBL Target CHEMBL2015 (Hs), CHEMBL3885583 (Mm), CHEMBL330 (Rn)
DrugBank Target Q05586 (Hs), Q05586 (Hs)
Ensembl Gene ENSG00000176884 (Hs), ENSMUSG00000026959 (Mm), ENSRNOG00000011726 (Rn)
Entrez Gene 2902 (Hs), 14810 (Mm), 24408 (Rn)
Human Protein Atlas ENSG00000176884 (Hs)
KEGG Gene hsa:2902 (Hs), mmu:14810 (Mm), rno:24408 (Rn)
OMIM 138249 (Hs)
Orphanet ORPHA282786 (Hs)
Pharos Q05586 (Hs)
RefSeq Nucleotide NM_007327 (Hs), NM_008169 (Mm), NM_017010 (Rn)
RefSeq Protein NP_015566 (Hs), NP_032195 (Mm), NP_058706 (Rn)
UniProtKB Q05586 (Hs), P35438 (Mm), P35439 (Rn)
Wikipedia GRIN1 (Hs)
Selected 3D Structures Click here for help
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 Click here for help
D-aspartic acid
D-serine
glycine
L-aspartic acid
L-glutamic acid

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
glycine Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist - -
⤷ [Binds to: glycine site]
L-aspartic acid Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist - -
⤷ [Binds to: glutamate site]
(+)-HA966 Small molecule or natural product Click here for species-specific activity table Hs Partial agonist - -
⤷ [Binds to: glycine site]
(RS)-(tetrazol-5-yl)glycine Small molecule or natural product Click here for species-specific activity table Hs Full agonist - -
⤷ [Binds to: glutamate site]
[3H]glycine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Ligand has a PDB structure Hs Full agonist - -
⤷ [Binds to: glycine site]
D-serine Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist - -
⤷ [Binds to: glycine site]
homoquinolinic acid Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist - -
⤷ [Binds to: glutamate site]
NMDA Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist - -
⤷ [Binds to: glutamate site]
D-aspartic acid Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure 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 Small molecule or natural product Ligand is labelled Ligand is radioactive Rn Antagonist ~8.5 pKd 1
⤷ pKd ~8.5 (Kd ~3x10-9 M) [Binds to: glycine site] [1]
GV196771A Small molecule or natural product 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} Small molecule or natural product Hs Antagonist 9.0 pIC50 3
⤷ pIC50 9.0 (IC50 1x10-9 M) [3]
L701324 Small molecule or natural product 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 Small molecule or natural product 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 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist - -
⤷ [Binds to: glycine site]
[3H]CGP39653 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist - -
⤷ [Binds to: glutamate site]
[3H]CGP61594 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist - -
⤷ [Binds to: glycine site] photoaffinity ligand
[3H]CGS19755 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist - -
⤷ [Binds to: glutamate site]
[3H]CPP Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist - -
⤷ [Binds to: glutamate site]
[3H]L689560 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist - -
⤷ [Binds to: glycine site]
[3H]dizocilpine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive 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 121-153 nM depending on the splice 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 Click here for help
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. (2020) Autoantibodies and Psychosis. Curr Top Behav Neurosci, 44: 85-123. [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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