Glutamate receptor ionotropic, NMDA 2A
Also known as: GRIN2A, NMDAR2A
Function
Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+). NMDARs participate in synaptic plasticity for learning and memory formation by contributing to the slow phase of excitatory postsynaptic current, long-term synaptic potentiation, and learning (By similarity). Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+). NMDARs mediate simultaneously the potassium efflux and the influx of calcium and sodium (By similarity). Each GluN2 subunit confers differential attributes to channel properties, including activation, deactivation and desensitization kinetics, pH sensitivity, Ca2(+) permeability, and binding to allosteric modulators. Participates in the synaptic plasticity regulation through activation by the L-glutamate releaseed by BEST1, into the synaptic cleft, upon F2R/PAR-1 activation in astrocyte (By similarity).
Classification
- Family (Pfam)
- PF01094 ANF_receptor, PF00060 Lig_chan, PF10613 Lig_chan-Glu_bd, PF10565 NMDAR2_C
- InterPro
- ANF_lig-bd_rcpt, Glu/Gly-bd, Iono_Glu_rcpt_met, Ionotropic_Glu_rcpt, Iontro_rcpt_C, NMDAR2_C, Peripla_BP_I
- Functional cluster
- Immunoglobulin-Domain Cell Adhesion Proteins
Experimental structures · PDB · 36
- 3NFL X-ray 1.91A
- 5H8F X-ray 1.81A
- 5H8H X-ray 2.23A
- 5H8N X-ray 2.50A
- 5H8Q X-ray 1.90A
- 5I2K X-ray 2.86A
- 5I2N X-ray 2.12A
- 5KCJ X-ray 2.09A
- 5KDT X-ray 2.44A
- 5TP9 X-ray 2.40A
- 5TPA X-ray 2.48A
- 6IRA EM 4.50A
- … and 24 more
A predicted model is available from AlphaFold.
Gene Ontology · 37
- GO:0009986 cell surface
- GO:0030659 cytoplasmic vesicle membrane
- GO:0043197 dendritic spine
- GO:0005789 endoplasmic reticulum membrane
- GO:0098978 glutamatergic synapse
- GO:0017146 NMDA selective glutamate receptor complex
- GO:0005886 plasma membrane
- GO:0014069 postsynaptic density
- GO:0098839 postsynaptic density membrane
- GO:0045211 postsynaptic membrane
- GO:0042734 presynaptic membrane
- GO:0097060 synaptic membrane
- GO:0008021 synaptic vesicle
- GO:0001540 amyloid-beta binding
- GO:0022849 glutamate-gated calcium ion channel activity
- GO:0004972 NMDA glutamate receptor activity
- GO:1904315 transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential
- GO:0008270 zinc ion binding
- GO:0007420 brain development
- GO:0097553 calcium ion transmembrane import into cytosol
- GO:0070588 calcium ion transmembrane transport
- GO:0007268 chemical synaptic transmission
- GO:0098976 excitatory chemical synaptic transmission
- GO:0060079 excitatory postsynaptic potential
- GO:0007215 glutamate receptor signaling pathway
- GO:0035235 ionotropic glutamate receptor signaling pathway
- GO:0007611 learning or memory
- GO:0060291 long-term synaptic potentiation
- GO:0098655 monoatomic cation transmembrane transport
- GO:2000463 positive regulation of excitatory postsynaptic potential
- GO:0051968 positive regulation of synaptic transmission, glutamatergic
- GO:1904062 regulation of monoatomic cation transmembrane transport
- GO:0048168 regulation of neuronal synaptic plasticity
- GO:0048167 regulation of synaptic plasticity
- GO:0045471 response to ethanol
- GO:0035725 sodium ion transmembrane transport
- GO:0035249 synaptic transmission, glutamatergic
Disease associations
Drugs targeting this protein · 21
- FELBAMATE antagonist
- ORPHENADRINE CITRATE antagonist
- ORPHENADRINE HYDROCHLORIDE antagonist
- GW468816 antagonist
- NEBOGLAMINE positive allosteric modulator
- DEXTROMETHORPHAN HYDROBROMIDE antagonist
- AMANTADINE HYDROCHLORIDE antagonist
- MEMANTINE HYDROCHLORIDE negative allosteric modulator
- KETAMINE HYDROCHLORIDE negative allosteric modulator
- ACAMPROSATE CALCIUM antagonist
- NERAMEXANE MESYLATE antagonist
- RALFINAMIDE antagonist
- DELUCEMINE antagonist
- ESKETAMINE HYDROCHLORIDE negative allosteric modulator
- RAPASTINEL partial agonist
- AV-101 antagonist
- ESKETAMINE negative allosteric modulator
- APIMOSTINEL partial agonist
- CNS-5161 blocker
- PERZINFOTEL antagonist
- LANICEMINE blocker
Related proteins · sequence + function similarity
- Glutamate receptor ionotropic, NMDA 2A 1.00
- Glutamate receptor ionotropic, NMDA 2A 1.00
- Glutamate receptor ionotropic, NMDA 2A 0.98
- Glutamate receptor ionotropic, NMDA 2B 0.95
- Glutamate receptor ionotropic, NMDA 2B 0.93
- Glutamate receptor ionotropic, NMDA 2B 0.93
- Glutamate receptor ionotropic, NMDA 2B 0.93
- Glutamate receptor ionotropic, NMDA 2B 0.93
- Glutamate [NMDA] receptor subunit 1 0.82
- Glutamate [NMDA] receptor subunit 1 0.82
- Glutamate [NMDA] receptor subunit 1 0.82
- Glutamate [NMDA] receptor subunit 1 0.82
Co-cited proteins · studied together in the literature
- Glutamate receptor ionotropic, NMDA 2B 10 shared papers
- Glutamate receptor ionotropic, NMDA 1 8 shared papers
- Glutamate receptor ionotropic, NMDA 2D 4 shared papers
- Transformation/transcription domain-associated protein 1 shared papers
- Serine/threonine-protein kinase B-raf 1 shared papers
- Glutamate receptor ionotropic, NMDA 2C 2 shared papers
- Glutamate receptor ionotropic, NMDA 2C 2 shared papers
- Glutamate receptor ionotropic, NMDA 3B 1 shared papers
- Activity-dependent neuroprotector homeobox protein 1 shared papers
- Glutamate receptor ionotropic, NMDA 3A 1 shared papers
- Voltage-dependent T-type calcium channel subunit alpha-1H 2 shared papers
- Phospholipid-transporting ATPase VA 1 shared papers
Literature · 32 cited papers
- De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor. Cell. Mol. Life Sci. · 2024
- Differential functional consequences of GRIN2A mutations associated with schizophrenia and neurodevelopmental disorders. Sci. Rep. · 2024
- Complex functional phenotypes of NMDA receptor disease variants. Mol. Psychiatry · 2022
- Rare coding variants in ten genes confer substantial risk for schizophrenia. Nature · 2022
- Gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors. Neuron · 2021
- GRIN2A-related disorders: genotype and functional consequence predict phenotype. Brain · 2019
- A novel missense mutation in GRIN2A causes a nonepileptic neurodevelopmental disorder. Mov. Disord. · 2018
- Epilepsy-associated GRIN2A mutations reduce NMDA receptor trafficking and agonist potency - molecular profiling and functional rescue. Sci. Rep. · 2017
- A de novo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia. PLoS ONE · 2017
- Functional evaluation of a de novo GRIN2A mutation identified in a patient with profound global developmental delay and refractory epilepsy. Mol. Pharmacol. · 2017
- GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive Allosteric Modulators with an Improved in Vivo Profile. ACS Med. Chem. Lett. · 2017
- Molecular mechanism of disease-associated mutations in the pre-M1 helix of NMDA receptors and potential rescue pharmacology. PLoS Genet. · 2017
- … and 20 more in the literature graph