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GluN2A

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Target id: 456

Nomenclature: GluN2A

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 1464 16p13.2 GRIN2A glutamate ionotropic receptor NMDA type subunit 2A
Mouse 3 1 1464 16 5.28 cM Grin2a glutamate receptor, ionotropic, NMDA2A (epsilon 1)
Rat 3 1 1464 10q11 Grin2a glutamate ionotropic receptor NMDA type subunit 2A
Previous and Unofficial Names Click here for help
NMDAR2A | GluRepsilon1 | NMDA-R2A | glutamate receptor, ionotropic, N-methyl D-aspartate 2A | glutamate receptor, ionotropic, NMDA2A (epsilon 1) | glutamate receptor
Database Links Click here for help
Alphafold Q12879 (Hs), P35436 (Mm), Q00959 (Rn)
ChEMBL Target CHEMBL1972 (Hs), CHEMBL3832634 (Mm), CHEMBL310 (Rn)
DrugBank Target Q12879 (Hs), Q12879 (Hs)
Ensembl Gene ENSG00000183454 (Hs), ENSMUSG00000059003 (Mm), ENSRNOG00000033942 (Rn)
Entrez Gene 2903 (Hs), 14811 (Mm), 24409 (Rn)
Human Protein Atlas ENSG00000183454 (Hs)
KEGG Gene hsa:2903 (Hs), mmu:14811 (Mm), rno:24409 (Rn)
OMIM 138253 (Hs)
Orphanet ORPHA289276 (Hs)
Pharos Q12879 (Hs)
RefSeq Nucleotide NM_000833 (Hs), NM_008170 (Mm), NM_012573 (Rn)
RefSeq Protein NP_000824 (Hs), NP_032196 (Mm), NP_036705 (Rn)
UniProtKB Q12879 (Hs), P35436 (Mm), Q00959 (Rn)
Wikipedia GRIN2A (Hs)
Natural/Endogenous Ligands Click here for help
D-aspartic acid
D-serine
glycine
L-aspartic acid
L-glutamic acid

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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] GluN2D > GluN2C > GluN2B > GluN2A
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] GluN2D = GluN2B > GluN2C = GluN2A
(+)-HA966 Small molecule or natural product Click here for species-specific activity table Hs Partial agonist - -
⤷ [Binds to: glycine site] GluN2B > GluN2A
(RS)-(tetrazol-5-yl)glycine Small molecule or natural product Click here for species-specific activity table Hs Full agonist - -
⤷ [Binds to: glutamate site] GluN2D > GluN2C = GluN2B > GluN2A
[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 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] GluN2D > GluN2C > GluN2B > GluN2A
homoquinolinic acid Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist - -
⤷ [Binds to: glutamate site] GluN2B ≥ GluN2A ≥ GluN2D > GluN2C; partial agonist at GluN2A and GluN2C
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] GluN2D > GluN2C > GluN2B > GluN2A
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] GluN2D > GluN2C = GluN2B > GluN2A
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
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] [3H]CGP61594 is a 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]MDL105519 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist - -
⤷ [Binds to: glycine site]
CGP37849 Small molecule or natural product Click here for species-specific activity table Hs Antagonist - -
⤷ [Binds to: glutamate site]
selfotel Small molecule or natural product Click here for species-specific activity table Hs Antagonist - -
⤷ [Binds to: glutamate site]
conantokin-G Peptide Click here for species-specific activity table Hs Antagonist - -
⤷ [Binds to: glutamate site] GluN2B > GluN2D = GluN2C = GluN2A
d-AP5 Small molecule or natural product Click here for species-specific activity table Hs Antagonist - -
⤷ [Binds to: glutamate site]
d-CCPene Small molecule or natural product Click here for species-specific activity table Hs Antagonist - -
⤷ [Binds to: glutamate site] GluN2A = GluN2B > GluN2C = GluN2D
GV196771A Small molecule or natural product Click here for species-specific activity table Hs Antagonist - -
⤷ [Binds to: glycine site]
L689560 Small molecule or natural product Click here for species-specific activity table Hs Antagonist - -
⤷ [Binds to: glycine site]
L701324 Small molecule or natural product Click here for species-specific activity table Hs Antagonist - -
⤷ [Binds to: glycine site]
LY233053 Small molecule or natural product Click here for species-specific activity table Hs Antagonist - -
⤷ [Binds to: glutamate site]
NVP-AAM077 Small molecule or natural product Click here for species-specific activity table Hs Antagonist - - 1-3,9
⤷ [Binds to: glutamate site] GluN2A > GluN2B (human), but weakly selective for rat GluN2A versus GluN2B [1-3,9]
UBP141 Small molecule or natural product Click here for species-specific activity table Hs Antagonist - - 8
⤷ [Binds to: glutamate site] GluN2D ≥ GluN2C > GluN2A ≥ GluN2B [8]
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Use-dependent Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
Mg2+ Click here for species-specific activity table Hs - no - - - no
⤷ GluN2A = GluN2B > GluN2C = GluN2D
Not voltage dependent
dizocilpine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs - no - - - no
⤷
Not voltage dependent
[3H]dizocilpine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs - no - - - no
⤷ [Binds to: cation channel]
Not voltage dependent
amantadine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs - no - - - no
⤷ GluN2C = GluN2D ≥ GluN2B ≥ GluN2A
Not voltage dependent
ketamine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs - no - - - no
⤷
Not voltage dependent
N1-dansyl-spermine Small molecule or natural product Click here for species-specific activity table Hs - no - - - no
⤷ GluN2A = GluN2B >> GluN2C = GluN2D
Not voltage dependent
phencyclidine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs - no - - - no
⤷
Not voltage dependent
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
NYX-2925 Small molecule or natural product Hs Positive 10.3 pEC50 - no 6
⤷ pEC50 10.3 (EC50 5.5x10-11 M) [6]
Not voltage dependent
Description: Potentiation of glycine site agonist MK-801 binding to human N-methyl-D-aspartate receptor NR2A-D subtypes expressed in HEK cells.
SAGE-718 Small molecule or natural product Click here for species-specific activity table Hs Positive 7.1 pEC50 - no 5
⤷ pEC50 7.1 (EC50 8.6x10-8 M) [5]
Not voltage dependent
Description: Value obtained using automated patch clamp electrophysiology in HEK293 cells stably expressing recombinant human GluN1/GluN2A Rs
plazinemdor Small molecule or natural product Hs Positive 6.4 pEC50 - no 10
⤷ pEC50 6.4 (EC50 4.39x10-7 M) [10]
Not voltage dependent
Description: Determined in a 2-electrode voltage clamp system using oocytes expressing hNR2A and activated with glutamate and glycine.
TCN-201 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Negative 7.0 pIC50 - no 4
⤷ pIC50 7.0 (IC50 1x10-7 M) [4]
Not voltage dependent
Description: Inhibition of glycine-induced (1µM) NMDA receptor responses measured in Xenopus oocytes co-expressing hGluN1 and hGluN2A NMDA receptor subunits
TCN-213 Small molecule or natural product Rn Negative 6.3 pIC50 - no 7
⤷ pIC50 6.3 (IC50 5.5x10-7 M) [7]
Not voltage dependent
Description: Inhibition of glycine-induced activation of GluN1/GluN2A NMDA channels in vitro
View species-specific allosteric modulator tables
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Epilepsy, focal, with speech disorder and with or without mental retardation; FESD
Synonyms: Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation [Orphanet: ORPHA289266]
OMIM: 245570
Orphanet: ORPHA289266
Disease:  Epileptic encephalopathy with continuous spike-and-wave during sleep
OMIM: 245570
Orphanet: ORPHA725
Disease:  Landau-Kleffner syndrome
Disease Ontology: DOID:2538
OMIM: 245570
Orphanet: ORPHA98818
Disease:  Rolandic epilepsy
Synonyms: Benign familial epilepsy of childhood with rolandic spikes [Orphanet: ORPHA1945]
OMIM: 245570
Orphanet: ORPHA1945
Disease:  Rolandic epilepsy - speech dyspraxia
OMIM: 245570
Orphanet: ORPHA163721

References

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1. Auberson YP, Allgeier H, Bischoff S, Lingenhoehl K, Moretti R, Schmutz M. (2002) 5-Phosphonomethylquinoxalinediones as competitive NMDA receptor antagonists with a preference for the human 1A/2A, rather than 1A/2B receptor composition. Bioorg Med Chem Lett, 12 (7): 1099-102. [PMID:11909726]

2. Feng B, Tse HW, Skifter DA, Morley R, Jane DE, Monaghan DT. (2004) Structure-activity analysis of a novel NR2C/NR2D-preferring NMDA receptor antagonist: 1-(phenanthrene-2-carbonyl) piperazine-2,3-dicarboxylic acid. Br J Pharmacol, 141 (3): 508-16. [PMID:14718249]

3. Frizelle PA, Chen PE, Wyllie DJ. (2006) Equilibrium constants for (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid (NVP-AAM077) acting at recombinant NR1/NR2A and NR1/NR2B N-methyl-D-aspartate receptors: Implications for studies of synaptic transmission. Mol Pharmacol, 70 (3): 1022-32. [PMID:16778008]

4. Hansen KB, Ogden KK, Traynelis SF. (2012) Subunit-selective allosteric inhibition of glycine binding to NMDA receptors. J Neurosci, 32 (18): 6197-208. [PMID:22553026]

5. Hill MD, Blanco MJ, Salituro FG, Bai Z, Beckley JT, Ackley MA, Dai J, Doherty JJ, Harrison BL, Hoffmann EC et al.. (2022) SAGE-718: A First-in-Class N-Methyl-d-Aspartate Receptor Positive Allosteric Modulator for the Potential Treatment of Cognitive Impairment. J Med Chem, 65 (13): 9063-9075. [PMID:35785990]

6. Khan MA, Houck DR, Gross AL, Zhang XL, Cearley C, Madsen TM, Kroes RA, Stanton PK, Burgdorf J, Moskal JR. (2018) NYX-2925 Is a Novel NMDA Receptor-Specific Spirocyclic-β-Lactam That Modulates Synaptic Plasticity Processes Associated with Learning and Memory. Int J Neuropsychopharmacol, 21 (3): 242-254. [PMID:29099938]

7. McKay S, Griffiths NH, Butters PA, Thubron EB, Hardingham GE, Wyllie DJ. (2012) Direct pharmacological monitoring of the developmental switch in NMDA receptor subunit composition using TCN 213, a GluN2A-selective, glycine-dependent antagonist. Br J Pharmacol, 166 (3): 924-37. [PMID:22022974]

8. Morley RM, Tse HW, Feng B, Miller JC, Monaghan DT, Jane DE. (2005) Synthesis and pharmacology of N1-substituted piperazine-2,3-dicarboxylic acid derivatives acting as NMDA receptor antagonists. J Med Chem, 48 (7): 2627-37. [PMID:15801853]

9. Neyton J, Paoletti P. (2006) Relating NMDA receptor function to receptor subunit composition: limitations of the pharmacological approach. J Neurosci, 26 (5): 1331-3. [PMID:16452656]

10. Volkmann RA, Anderson DR, Melekiani S, Piser T, Keaney GF, Leiser SC. (2020) Heteroaromatic nmda receptor modulators and uses thereof. Patent number: WO2020086136A2. Assignee: Cadent Therapeutics, Inc.. Priority date: 03/08/2018. Publication date: 30/04/2020.

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