GRIN1 encodes GluN1, the obligatory subunit of NMDA-type ionotropic glutamate receptors. Two GluN1 subunits assemble with two GluN2 (A-D) and/or GluN3 (A-B) subunits into a heterotetrameric cation channel in the neuronal plasma membrane, concentrated in the postsynaptic density of excitatory synapses on dendritic spines. GluN1 binds the co-agonist glycine or D-serine, while GluN2 subunits bind glutamate; opening of GluN1/GluN2 channels also requires depolarisation to relieve voltage-dependent Mg2+ block, so the receptor detects coincident pre- and postsynaptic activity. The open channel conducts Na+, K+ and Ca2+, and the calcium influx triggers long-term changes in synaptic strength that underlie learning and memory. With GluN3 subunits, GluN1 instead forms glycine-gated cation channels with low calcium permeability. Its C-terminal tail binds calmodulin. De novo and biallelic GRIN1 variants cause a neurodevelopmental disorder with intellectual disability, movement abnormalities and seizures.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001540 amyloid-beta binding | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Transferred from rat GluN1 (PMID:17308309), where an antibody to the NR1 extracellular domain reduced binding of amyloid-beta oligomers to neurons and the oligomers co-immunoprecipitated with NMDA receptor subunits. Reason: The donor study does not show that GluN1 itself binds amyloid-beta: the authors conclude only that the oligomers bind to or near NMDA receptors. A direct binding function for GluN1 goes beyond that evidence. Supporting Evidence: PMID:17308309 ADDLs bind to or in close proximity to NMDA-Rs, triggering neuronal damage through NMDA-R-dependent calcium flux |
| GO:0004972 NMDA glutamate receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT places NMDA receptor activity at PTN001451205, the GluN1 clade, seeded by fly Nmdar1 and by human GRIN1 itself. Reason: GluN1 is the obligatory glycine-binding subunit of every NMDA receptor, so the human protein sits inside the clade that inherited the activity and has its own experimental grounding (PMID:7679115, PMID:7685113). The contributes_to form is the accurate one: the channel needs a GluN2 partner. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt 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+) PMID:7679115 Expression in Xenopus oocytes demonstrated that the single protein encoded by the cloned cDNA possesses the electrophysiological and pharmacological properties characteristic of the NMDA receptor, including Ca2+ permeability, voltage-dependent Mg2+ block, and inhibition by selective antagonists such as Zn2+ and channel blockers |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:24272827 GRIN2B mutations in West syndrome and intellectual disabilit... | ACCEPT | Summary: Human NR1 was co-expressed with wild-type or mutant NR2B in Xenopus oocytes; GluN1 is the constant subunit of the channels whose Mg2+ block and Ca2+ permeability were measured. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. Supporting Evidence: PMID:24272827 Mutations p.Asn615Ile and p.Val618Gly cause a significantly reduced Mg(2+) block and higher Ca(2+) permeability, leading to a dramatically increased Ca(2+) influx file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:24272827 GRIN2B mutations in West syndrome and intellectual disabilit... | ACCEPT | Summary: Human NR1 was co-expressed with wild-type or mutant NR2B in Xenopus oocytes; GluN1 is the constant subunit of the channels whose Mg2+ block and Ca2+ permeability were measured. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. Supporting Evidence: PMID:24272827 Mutations p.Asn615Ile and p.Val618Gly cause a significantly reduced Mg(2+) block and higher Ca(2+) permeability, leading to a dramatically increased Ca(2+) influx file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:26875626 Positive Allosteric Modulators of GluN2A-Containing NMDARs w... | ACCEPT | Summary: Recombinant GluN1/GluN2A receptors were used to characterise GluN2A-selective positive allosteric modulators that bind at the GluN1-GluN2A ligand-binding-domain interface. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. Supporting Evidence: PMID:26875626 Potentiation was observed with recombinant triheteromeric GluN1/GluN2A/GluN2B NMDARs and with synaptically activated NMDARs in brain slices file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:26919761 Discovery of GluN2A-Selective NMDA Receptor Positive Alloste... | ACCEPT | Summary: Recombinant GluN1/GluN2A receptors were used for electrophysiology and crystallography of GluN2A-selective potentiators. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. Supporting Evidence: PMID:26919761 The N-methyl-D-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable ionotropic glutamate receptor that is activated by the coagonists glycine and glutamate file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:27164704 Delineating the GRIN1 phenotypic spectrum: A distinct geneti... | ACCEPT | Summary: Disease-associated GRIN1 variants were tested by co-expressing GluN1 with GluN2B in Xenopus oocytes. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. Supporting Evidence: PMID:27164704 Functional consequences of GRIN1 mutations were investigated in Xenopus laevis oocytes file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:28095420 Molecular Mechanism of Disease-Associated Mutations in the P... | ACCEPT | Summary: Pre-M1 helix variants, including GRIN1 variants, were assayed in recombinant GluN1/GluN2 receptors. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. Supporting Evidence: PMID:28095420 GluN2A-P552R and analogous mutations in other GluN subunits increased the agonist potency and slowed response time course file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:28105280 GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive... | ACCEPT | Summary: Recombinant GluN1/GluN2A receptors were used to characterise a second GluN2A-selective potentiator series. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. Supporting Evidence: PMID:28105280 The N-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca2+ and Na+ file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:28126851 Functional Evaluation of a De Novo GRIN2A Mutation Identifie... | ACCEPT | Summary: Human GluN1 was co-expressed with wild-type or M817V GluN2A to measure agonist potency, Mg2+, proton and zinc sensitivity and single-channel properties. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. Supporting Evidence: PMID:28126851 the mutant GluN2A(M817V)-containing receptors showed enhanced agonist potency, reduced sensitivity to endogenous negative inhibitors (Mg2+, proton, and zinc) file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:28228639 GRIN1 mutation associated with intellectual disability alter... | ACCEPT | Summary: GluN1-G620R co-expressed with GluN2A or GluN2B reduced agonist potency, Mg2+ block and current amplitude, showing that GluN1 pore residues set channel properties. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. Supporting Evidence: PMID:28228639 GluN1-G620R/GluN2A complexes showed a mild reduction in trafficking, a ~2-fold decrease in glutamate and glycine potency, a strong decrease in sensitivity to Mg2+ block file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:38538865 De novo GRIN variants in M3 helix associated with neurologic... | ACCEPT | Summary: M3-helix variants in GRIN1, GRIN2A and GRIN2B were assayed in recombinant receptors; M3 of GluN1 forms part of the channel gate. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. Supporting Evidence: PMID:38538865 we report the functional consequences of 48 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M3 transmembrane helix file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:7679115 Molecular cloning and chromosomal localization of the key su... | ACCEPT | Summary: The cloned human NMDAR1 cDNA produced currents in Xenopus oocytes with Ca2+ permeability, voltage-dependent Mg2+ block and block by NMDA receptor antagonists. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. The small currents seen with NR1 alone in oocytes are generally attributed to assembly with an endogenous Xenopus GluN2 subunit, which does not change the conclusion for this term. Supporting Evidence: PMID:7679115 Expression in Xenopus oocytes demonstrated that the single protein encoded by the cloned cDNA possesses the electrophysiological and pharmacological properties characteristic of the NMDA receptor, including Ca2+ permeability, voltage-dependent Mg2+ block, and inhibition by selective antagonists such as Zn2+ and channel blockers file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:7681588 Inducible expression of neuronal glutamate receptor channels... | ACCEPT | Summary: Retinoic-acid-differentiated human NT2 cells expressed NMDA receptor channels, with subunit expression shown by PCR and currents by patch clamp. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. Supporting Evidence: PMID:7681588 cells from the human teratocarcinoma line NT2 are induced by retinoic acid to express neuronal N-methyl-D-aspartate (NMDA) and non-NMDA GluR channels file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:7685113 Molecular cloning, functional expression, and pharmacologica... | ACCEPT | Summary: Human hNR1 cRNA gave glutamate- and NMDA-activated, glycine-dependent currents in oocytes with the pharmacology of NMDA receptors. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. The small currents seen with NR1 alone in oocytes are generally attributed to assembly with an endogenous Xenopus GluN2 subunit, which does not change the conclusion for this term. Supporting Evidence: PMID:7685113 Oocytes injected with cRNA synthesized from the hNR1 cDNA express glutamate and NMDA-activated currents in the presence of glycine file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:7685113 Molecular cloning, functional expression, and pharmacologica... | ACCEPT | Summary: Human hNR1 cRNA gave glutamate- and NMDA-activated, glycine-dependent currents in oocytes with the pharmacology of NMDA receptors. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. The small currents seen with NR1 alone in oocytes are generally attributed to assembly with an endogenous Xenopus GluN2 subunit, which does not change the conclusion for this term. Supporting Evidence: PMID:7685113 Oocytes injected with cRNA synthesized from the hNR1 cDNA express glutamate and NMDA-activated currents in the presence of glycine file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:9489750 Functional characterization of human N-methyl-D-aspartate su... | ACCEPT | Summary: Human NMDAR1A co-expressed with NMDAR2D (or 2A, 2B, 2C) gave receptors with subtype-specific agonist and antagonist potencies. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. Supporting Evidence: PMID:9489750 glutamate, NMDA, glycine, and D-serine were significantly more potent on hNMDAR1A/2D than on hNMDAR1A/2A or hNMDAR1A/2B file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IDA PMID:9489750 Functional characterization of human N-methyl-D-aspartate su... | ACCEPT | Summary: Human NMDAR1A co-expressed with NMDAR2D (or 2A, 2B, 2C) gave receptors with subtype-specific agonist and antagonist potencies. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. Supporting Evidence: PMID:9489750 glutamate, NMDA, glycine, and D-serine were significantly more potent on hNMDAR1A/2D than on hNMDAR1A/2A or hNMDAR1A/2B file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | IEA GO_REF:0000117 | ACCEPT | Summary: NMDA receptor activity transferred from the ARBA model; it restates the experimentally established activity of GluN1-containing receptors. Reason: Human GluN1 forms glutamate- and glycine-gated, calcium-permeable, Mg2+-blocked channels with GluN2 subunits, shown directly with the human cDNA. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt 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+) PMID:7679115 Expression in Xenopus oocytes demonstrated that the single protein encoded by the cloned cDNA possesses the electrophysiological and pharmacological properties characteristic of the NMDA receptor, including Ca2+ permeability, voltage-dependent Mg2+ block, and inhibition by selective antagonists such as Zn2+ and channel blockers |
| GO:0004972 NMDA glutamate receptor activity | IMP PMID:28228639 GRIN1 mutation associated with intellectual disability alter... | ACCEPT | Summary: GluN1-G620R co-expressed with GluN2A or GluN2B reduced agonist potency, Mg2+ block and current amplitude, showing that GluN1 pore residues set channel properties. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. Supporting Evidence: PMID:28228639 GluN1-G620R/GluN2A complexes showed a mild reduction in trafficking, a ~2-fold decrease in glutamate and glycine potency, a strong decrease in sensitivity to Mg2+ block file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0004972 NMDA glutamate receptor activity | ISS GO_REF:0000024 | ACCEPT | Summary: NMDA receptor activity transferred from rat GluN2A (Q00959); it restates the experimentally established activity of GluN1-containing receptors. Reason: Human GluN1 forms glutamate- and glycine-gated, calcium-permeable, Mg2+-blocked channels with GluN2 subunits, shown directly with the human cDNA. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt 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+) PMID:7679115 Expression in Xenopus oocytes demonstrated that the single protein encoded by the cloned cDNA possesses the electrophysiological and pharmacological properties characteristic of the NMDA receptor, including Ca2+ permeability, voltage-dependent Mg2+ block, and inhibition by selective antagonists such as Zn2+ and channel blockers |
| GO:0004972 NMDA glutamate receptor activity | TAS PMID:17526495 Fyn-mediated phosphorylation of NR2B Tyr-1336 controls calpa... | ACCEPT | Summary: A TAS statement from a paper that recorded wild-type and calpain-truncated NR1/NR2B receptors. Reason: GluN1 is a pore-forming, glycine-binding subunit of the receptor measured here. The activity belongs to the GluN1/GluN2 heterotetramer, so the enables and contributes_to rows describe the same fact and are both kept. Supporting Evidence: PMID:17526495 truncated NR1/2B receptors similar to those generated by calpain have electrophysiological properties matching those of wild-type receptors file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0005216 monoatomic ion channel activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping from ionotropic glutamate receptor signatures. Reason: True of GluN1 but less specific than the evidence. NMDA glutamate receptor activity is a descendant of this term and GRIN1 carries it with direct experimental support; with GluN3 partners the specific activity is glycine-gated cation channel activity, also a descendant. Proposed replacements: NMDA glutamate receptor activity glycine-gated cation channel activity Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt 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+) PMID:11823786 NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA |
| GO:0005262 calcium channel activity | IDA PMID:7685113 Molecular cloning, functional expression, and pharmacologica... | MODIFY | Summary: hNR1-containing channels expressed in oocytes showed high Ca2+ permeability. Reason: Correct but less specific than the evidence: the calcium flux is through a glutamate-gated channel. GO:0022849 is an is_a descendant of calcium channel activity and GRIN1 already carries it. Proposed replacements: glutamate-gated calcium ion channel activity Supporting Evidence: PMID:7685113 Expressed hNR1 homomeric receptor channels exhibit the high Ca2+ permeability characteristic of neuronal NMDA receptors |
| GO:0005509 calcium ion binding | ISS GO_REF:0000024 | UNDECIDED | Summary: Transferred from mouse GluN1 (PMID:15663482), a study of myosin regulatory light chain binding to the NR1 C0 region. Reason: The accessible abstract shows a calcium dependence of calmodulin competition, not calcium binding by NR1 itself; the full text is not available here, so the donor assertion cannot be confirmed or excluded. Supporting Evidence: PMID:15663482 Ca2+/calmodulin, but not calmodulin alone, displaced recombinant myosin RLC from the carboxy tail of NR1 |
| GO:0005515 protein binding | IPI PMID:17047094 Subunit-specific roles of glycine-binding domains in activat... | REMOVE | Summary: Interaction of GluN1 with GRIN2B, a fellow NMDA receptor subunit. Reason: The association is real, but generic protein binding says nothing about function. Co-assembly with GluN2 and GluN3 subunits is already recorded by the NMDA receptor complex and receptor activity terms. Supporting Evidence: PMID:17047094 N-Methyl-D-aspartate receptors (NMDARs) composed of NR1 and NR3 subunits differ from other NMDAR subtypes in that they require glycine alone for activation file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0005515 protein binding | IPI PMID:17997397 Analysis of NR3A receptor subunits in human native NMDA rece... | REMOVE | Summary: Interaction of GluN1 with GRIN3A, a fellow NMDA receptor subunit. Reason: The association is real, but generic protein binding says nothing about function. Co-assembly with GluN2 and GluN3 subunits is already recorded by the NMDA receptor complex and receptor activity terms. Supporting Evidence: PMID:17997397 We found that NR3A is associated with NR1, NR2A and NR2B in adult human CNS, suggesting the existence of native NR1-NR2A/B-NR3A assemblies in adult human CNS file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Yeast two-hybrid interaction with APP from a neurodegenerative-disease interactome screen. Reason: A screen hit without follow-up that would indicate a specific molecular function for GluN1. Generic protein binding is uninformative; removing it does not dispute the reported interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Yeast two-hybrid interaction with FUS from a neurodegenerative-disease interactome screen. Reason: A screen hit without follow-up that would indicate a specific molecular function for GluN1. Generic protein binding is uninformative; removing it does not dispute the reported interaction. Supporting Evidence: |
| GO:0005516 calmodulin binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse GluN1 (PMID:15663482): Ca2+/calmodulin competes with myosin regulatory light chain for the C0 region of the NR1 C-terminal tail. Reason: Calmodulin binding to the GluN1 C-terminus is an established regulatory interaction that modulates the channel; it is not the core activity. Supporting Evidence: PMID:15663482 Ca2+/calmodulin, but not calmodulin alone, displaced recombinant myosin RLC from the carboxy tail of NR1 PMID:15663482 calmodulin which is considered a NR1-interacting protein |
| GO:0005737 cytoplasm | ISS PMID:17526495 Fyn-mediated phosphorylation of NR2B Tyr-1336 controls calpa... | KEEP AS NON CORE | Summary: Transferred from rat GluN1; the cited paper studied NR2B cleavage in neurons and HEK cells. Reason: GluN1 is an integral membrane protein, so the cytoplasmic signal reflects intracellular membrane-bound pools (biosynthetic and recycling), which have been described in spines. The compartment is not resolved further by the source, and this pool is not where the channel functions. Supporting Evidence: PMID:17207780 the cytoplasmic to synaptic ratios of GluRs were measured within thalamo-amygdaloid spines |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9609742 | MARK AS OVER ANNOTATED | Summary: Reactome places NMDA receptor subunit assembly, or the start of trafficking to the surface, in the endoplasmic reticulum membrane. Reason: GluN1 is made and assembled with GluN2 or GluN3 subunits in the ER, as every plasma membrane protein is, so the statement is not false. But the channel does not function there, and the row rests on assembly and transit, not on an assay showing the endogenous protein residing in the ER membrane of neurons. In mice lacking the main cerebellar GluN2 subunits, unassembled GluN1 was degraded faster and did not accumulate in the ER. An ER retention signal in the GluN1 C1 cassette has been described (PMID:11640925), but it was shown with an overexpressed CD8-NR1 fusion protein, which the ER rule does not count as residence of the endogenous protein. Under that rule (projects/ORGANELLES.md, rule 7) a transit-only row is an over-annotation. Supporting Evidence: Reactome:R-HSA-9609742 GluN2A (GRIN2A) forms a di-heterotetramer with GluN1 (GRIN1) PMID:15317856 The loss was not accompanied by decreased transcription and translation levels, increased extrasynaptic labeling, or ER accumulation PMID:11640925 the NR1 fusion protein was retained intracellularly in both HEK293 cells and neurons because of the presence of an ER retention signal in the C1 cassette |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9609743 | MARK AS OVER ANNOTATED | Summary: Reactome places NMDA receptor subunit assembly, or the start of trafficking to the surface, in the endoplasmic reticulum membrane. Reason: GluN1 is made and assembled with GluN2 or GluN3 subunits in the ER, as every plasma membrane protein is, so the statement is not false. But the channel does not function there, and the row rests on assembly and transit, not on an assay showing the endogenous protein residing in the ER membrane of neurons. In mice lacking the main cerebellar GluN2 subunits, unassembled GluN1 was degraded faster and did not accumulate in the ER. An ER retention signal in the GluN1 C1 cassette has been described (PMID:11640925), but it was shown with an overexpressed CD8-NR1 fusion protein, which the ER rule does not count as residence of the endogenous protein. Under that rule (projects/ORGANELLES.md, rule 7) a transit-only row is an over-annotation. Supporting Evidence: Reactome:R-HSA-9609743 GluN1 (GRIN1) binds to GluN2B (GRIN2B) and GluN3A (GRIN3A) to form a tri-heteromeric NMDA receptor PMID:15317856 The loss was not accompanied by decreased transcription and translation levels, increased extrasynaptic labeling, or ER accumulation PMID:11640925 the NR1 fusion protein was retained intracellularly in both HEK293 cells and neurons because of the presence of an ER retention signal in the C1 cassette |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9610750 | MARK AS OVER ANNOTATED | Summary: Reactome places NMDA receptor subunit assembly, or the start of trafficking to the surface, in the endoplasmic reticulum membrane. Reason: GluN1 is made and assembled with GluN2 or GluN3 subunits in the ER, as every plasma membrane protein is, so the statement is not false. But the channel does not function there, and the row rests on assembly and transit, not on an assay showing the endogenous protein residing in the ER membrane of neurons. In mice lacking the main cerebellar GluN2 subunits, unassembled GluN1 was degraded faster and did not accumulate in the ER. An ER retention signal in the GluN1 C1 cassette has been described (PMID:11640925), but it was shown with an overexpressed CD8-NR1 fusion protein, which the ER rule does not count as residence of the endogenous protein. Under that rule (projects/ORGANELLES.md, rule 7) a transit-only row is an over-annotation. Supporting Evidence: Reactome:R-HSA-9610750 are all delivered to the plasma membrane where they are anchored to postsynaptic density regions PMID:15317856 The loss was not accompanied by decreased transcription and translation levels, increased extrasynaptic labeling, or ER accumulation PMID:11640925 the NR1 fusion protein was retained intracellularly in both HEK293 cells and neurons because of the presence of an ER retention signal in the C1 cassette |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-NUL-9610202 | MARK AS OVER ANNOTATED | Summary: Reactome places NMDA receptor subunit assembly, or the start of trafficking to the surface, in the endoplasmic reticulum membrane. Reason: GluN1 is made and assembled with GluN2 or GluN3 subunits in the ER, as every plasma membrane protein is, so the statement is not false. But the channel does not function there, and the row rests on assembly and transit, not on an assay showing the endogenous protein residing in the ER membrane of neurons. In mice lacking the main cerebellar GluN2 subunits, unassembled GluN1 was degraded faster and did not accumulate in the ER. An ER retention signal in the GluN1 C1 cassette has been described (PMID:11640925), but it was shown with an overexpressed CD8-NR1 fusion protein, which the ER rule does not count as residence of the endogenous protein. Under that rule (projects/ORGANELLES.md, rule 7) a transit-only row is an over-annotation. Supporting Evidence: Reactome:R-NUL-9610202 Recombinant rat GluN2C (Grin2c) can bind recombinant human GluN1 (GRIN1) PMID:15317856 The loss was not accompanied by decreased transcription and translation levels, increased extrasynaptic labeling, or ER accumulation PMID:11640925 the NR1 fusion protein was retained intracellularly in both HEK293 cells and neurons because of the presence of an ER retention signal in the C1 cassette |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT places plasma membrane activity at PTN000437926, the root of the ionotropic glutamate receptor family. Reason: All members of the family are plasma membrane channels; shown directly for human GluN1. Supporting Evidence: PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0005886 plasma membrane | IDA PMID:26875626 Positive Allosteric Modulators of GluN2A-Containing NMDARs w... | ACCEPT | Summary: Receptors containing human GluN1 were expressed at, and recorded from, the plasma membrane of heterologous cells. Reason: The plasma membrane is where the channel is gated by extracellular agonists. Supporting Evidence: PMID:26875626 Potentiation was observed with recombinant triheteromeric GluN1/GluN2A/GluN2B NMDARs and with synaptically activated NMDARs in brain slices file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0005886 plasma membrane | IDA PMID:26919761 Discovery of GluN2A-Selective NMDA Receptor Positive Alloste... | ACCEPT | Summary: Receptors containing human GluN1 were expressed at, and recorded from, the plasma membrane of heterologous cells. Reason: The plasma membrane is where the channel is gated by extracellular agonists. Supporting Evidence: PMID:26919761 The N-methyl-D-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable ionotropic glutamate receptor that is activated by the coagonists glycine and glutamate file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0005886 plasma membrane | IDA PMID:28095420 Molecular Mechanism of Disease-Associated Mutations in the P... | ACCEPT | Summary: Receptors containing human GluN1 were expressed at, and recorded from, the plasma membrane of heterologous cells. Reason: The plasma membrane is where the channel is gated by extracellular agonists. Supporting Evidence: PMID:28095420 GluN2A-P552R and analogous mutations in other GluN subunits increased the agonist potency and slowed response time course file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0005886 plasma membrane | IDA PMID:28105280 GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive... | ACCEPT | Summary: Receptors containing human GluN1 were expressed at, and recorded from, the plasma membrane of heterologous cells. Reason: The plasma membrane is where the channel is gated by extracellular agonists. Supporting Evidence: PMID:28105280 The N-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca2+ and Na+ file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0005886 plasma membrane | IDA PMID:28126851 Functional Evaluation of a De Novo GRIN2A Mutation Identifie... | ACCEPT | Summary: Receptors containing human GluN1 were expressed at, and recorded from, the plasma membrane of heterologous cells. Reason: The plasma membrane is where the channel is gated by extracellular agonists. Supporting Evidence: PMID:28126851 the mutant GluN2A(M817V)-containing receptors showed enhanced agonist potency, reduced sensitivity to endogenous negative inhibitors (Mg2+, proton, and zinc) file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0005886 plasma membrane | IDA PMID:28228639 GRIN1 mutation associated with intellectual disability alter... | ACCEPT | Summary: Receptors containing human GluN1 were expressed at, and recorded from, the plasma membrane of heterologous cells. Reason: The plasma membrane is where the channel is gated by extracellular agonists. Supporting Evidence: PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0005886 plasma membrane | IDA PMID:38538865 De novo GRIN variants in M3 helix associated with neurologic... | ACCEPT | Summary: Receptors containing human GluN1 were expressed at, and recorded from, the plasma membrane of heterologous cells. Reason: The plasma membrane is where the channel is gated by extracellular agonists. Supporting Evidence: PMID:38538865 we report the functional consequences of 48 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M3 transmembrane helix file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0005886 plasma membrane | IDA PMID:7685113 Molecular cloning, functional expression, and pharmacologica... | ACCEPT | Summary: Receptors containing human GluN1 were expressed at, and recorded from, the plasma membrane of heterologous cells. Reason: The plasma membrane is where the channel is gated by extracellular agonists. Supporting Evidence: PMID:7685113 Oocytes injected with cRNA synthesized from the hNR1 cDNA express glutamate and NMDA-activated currents in the presence of glycine file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping. Reason: Human GluN1-containing receptors function at the plasma membrane. Supporting Evidence: PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0005886 plasma membrane | ISS GO_REF:0000114 | ACCEPT | Summary: Transferred from the GluN1-GluN2A complex entry. Reason: Human GluN1-containing receptors function at the plasma membrane. Supporting Evidence: PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0005886 plasma membrane | NAS PMID:34321660 Structural basis of ketamine action on human NMDA receptors. | ACCEPT | Summary: Author statement in a structural study of human GluN1-containing receptors. Reason: NMDA receptors are plasma membrane channels. Supporting Evidence: PMID:34321660 we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface |
| GO:0005886 plasma membrane | NAS PMID:36309015 Structural insights into assembly and function of GluN1-2C, ... | ACCEPT | Summary: Author statement in a structural study of human GluN1-containing receptors. Reason: NMDA receptors are plasma membrane channels. Supporting Evidence: PMID:36309015 NMDARs are glycine- and glutamate-gated ion channels that exist as heterotetramers composed of obligatory GluN1 and GluN2(A-D) and/or GluN3(A-B) PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface |
| GO:0005886 plasma membrane | NAS PMID:36959261 Distinct structure and gating mechanism in diverse NMDA rece... | ACCEPT | Summary: Author statement in a structural study of human GluN1-containing receptors. Reason: NMDA receptors are plasma membrane channels. Supporting Evidence: PMID:36959261 N-methyl-D-aspartate (NMDA) receptors are heterotetramers comprising two GluN1 and two alternate GluN2 (N2A-N2D) subunits PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3928627 | ACCEPT | Summary: Reactome places the NMDA receptor, including GluN1, at the plasma membrane in this reaction. Reason: Consistent with the site of channel function. Supporting Evidence: Reactome:R-HSA-3928627 Once recruited to the EPHB:NMDAR complex PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3928645 | ACCEPT | Summary: Reactome places the NMDA receptor, including GluN1, at the plasma membrane in this reaction. Reason: Consistent with the site of channel function. Supporting Evidence: Reactome:R-HSA-3928645 TIAM1 is recruited to EPHB complexes containing NMDAR after EPHB receptor activation in neurons PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-4093336 | ACCEPT | Summary: Reactome places the NMDA receptor, including GluN1, at the plasma membrane in this reaction. Reason: Consistent with the site of channel function. Supporting Evidence: Reactome:R-HSA-4093336 bound to EPHB complexes containing NMDARs PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-432164 | ACCEPT | Summary: Reactome places the NMDA receptor, including GluN1, at the plasma membrane in this reaction. Reason: Consistent with the site of channel function. Supporting Evidence: Reactome:R-HSA-432164 The activation leads to Ca2+ influx into the post-synaptic cell PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5672965 | ACCEPT | Summary: Reactome places the NMDA receptor, including GluN1, at the plasma membrane in this reaction. Reason: Consistent with the site of channel function. Supporting Evidence: Reactome:R-HSA-5672965 Reactome:R-HSA-9610750 are all delivered to the plasma membrane where they are anchored to postsynaptic density regions PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8849878 | ACCEPT | Summary: Reactome places the NMDA receptor, including GluN1, at the plasma membrane in this reaction. Reason: Consistent with the site of channel function. Supporting Evidence: Reactome:R-HSA-8849878 N-methyl-D-aspartate (NMDA) receptor interact with postsynaptic density protein (PSD-95) PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8849881 | ACCEPT | Summary: Reactome places the NMDA receptor, including GluN1, at the plasma membrane in this reaction. Reason: Consistent with the site of channel function. Supporting Evidence: Reactome:R-HSA-8849881 SALM2 coimmunoprecipitates with NMDAR and AMPAR subunits isolated from detergent-solubilized brain PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8849906 | ACCEPT | Summary: Reactome places the NMDA receptor, including GluN1, at the plasma membrane in this reaction. Reason: Consistent with the site of channel function. Supporting Evidence: Reactome:R-HSA-8849906 SALM1 can directly interact with the extracellular domain of the NR1 subunit of NMDA receptor PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9610750 | ACCEPT | Summary: Reactome places the NMDA receptor, including GluN1, at the plasma membrane in this reaction. Reason: Consistent with the site of channel function. Supporting Evidence: Reactome:R-HSA-9610750 are all delivered to the plasma membrane where they are anchored to postsynaptic density regions PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface |
| GO:0006811 monoatomic ion transport | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping. Reason: Correct but general. The channel moves cations across the membrane, which the descendant term monoatomic cation transmembrane transport, already carried by GRIN1, states precisely. Proposed replacements: monoatomic cation transmembrane transport Supporting Evidence: PMID:7685113 Expressed hNR1 homomeric receptor channels exhibit the high Ca2+ permeability characteristic of neuronal NMDA receptors file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0006812 monoatomic cation transport | IDA PMID:7685113 Molecular cloning, functional expression, and pharmacologica... | MODIFY | Summary: hNR1-containing channels conducted cations in oocytes. Reason: Correct but general. The channel moves cations across the membrane, which the descendant term monoatomic cation transmembrane transport, already carried by GRIN1, states precisely. Proposed replacements: monoatomic cation transmembrane transport Supporting Evidence: PMID:7685113 Expressed hNR1 homomeric receptor channels exhibit the high Ca2+ permeability characteristic of neuronal NMDA receptors file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0007268 chemical synaptic transmission | IBA GO_REF:0000033 | MODIFY | Summary: PAINT annotation at PTN001451205 (GluN1 clade), seeded by fly Nmdar1 and mouse Grin1. Reason: Correct but general. NMDA receptors act in excitatory transmission, a descendant term GRIN1 already carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001451205 Β· PANTHER:PTN001451205 SUPPORTS TRANSFER GluN1 clade node seeded by fly Nmdar1, mouse Grin1 and rat Grin1. The node placement is sound; the term is simply broader than what is established for GluN1, and the specific descendant is already annotated. Proposed replacements: excitatory chemical synaptic transmission Supporting Evidence: PMID:8980238 Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0007420 brain development | NAS PMID:17526495 Fyn-mediated phosphorylation of NR2B Tyr-1336 controls calpa... | KEEP AS NON CORE | Summary: Author statement in a paper on NR2B cleavage; no experiment on brain development in that study. Reason: NMDA receptors are needed for normal brain development and pathogenic GRIN1 variants cause a neurodevelopmental disorder, but this is a consequence of the channel function at the organism level, not a separate activity of the protein. Supporting Evidence: PMID:28228639 N-methyl-d-aspartate receptors (NMDARs) play important roles in brain development and neurological disease PMID:27164704 we describe 2 homozygous GRIN1 mutations (1 missense, 1 truncation), each segregating with severe neurodevelopmental phenotypes in consanguineous families |
| GO:0008021 synaptic vesicle | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Transferred from mouse GluN1 (PMID:10846156), which describes KIF17-driven transport of NMDA receptor-containing vesicles along dendritic microtubules. Reason: The vesicles in the donor study are dendritic transport carriers for receptor delivery, not neurotransmitter-filled synaptic vesicles of the presynaptic terminal, so the term does not fit the observation. Supporting Evidence: PMID:10846156 vesicles containing N-methyl-D-aspartate (NMDA) receptor 2B (NR2B subunit) show that they are transported along microtubules by KIF17 |
| GO:0008542 visual learning | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from mouse Grin1 mutant phenotypes (for example PMID:8980238). Reason: The mouse annotations rest on spatial-memory tasks that depend on visual cues; mice lacking the gene in CA1 are impaired in them, while nonspatial learning is spared. This is an organism-level consequence of lost NMDA receptor-dependent plasticity, not a distinct molecular role. Supporting Evidence: PMID:8980238 exhibit impaired spatial memory |
| GO:0009986 cell surface | ISS GO_REF:0000024 | ACCEPT | Summary: Surface expression of GluN1-containing receptors, transferred from mouse and rat GluN1. Reason: NMDA receptors act at the neuronal surface; surface delivery of human GluN1 with GluN2 partners has been measured directly. Supporting Evidence: PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface |
| GO:0009986 cell surface | ISS PMID:17526495 Fyn-mediated phosphorylation of NR2B Tyr-1336 controls calpa... | ACCEPT | Summary: Surface expression of GluN1-containing receptors, transferred from mouse and rat GluN1. Reason: NMDA receptors act at the neuronal surface; surface delivery of human GluN1 with GluN2 partners has been measured directly. Supporting Evidence: PMID:17526495 The potentiation of NR2B cleavage by Fyn is limited to cell surface receptors PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface |
| GO:0010524 positive regulation of calcium ion transport into cytosol | ISS GO_REF:0000024 | MODIFY | Summary: Transferred from rat GluN1 (PMID:17308309): the amyloid-beta-induced rise in neuronal calcium was attenuated by memantine and by an anti-NR1 antibody. Reason: The NMDA receptor does not regulate calcium entry, it is the channel through which the calcium enters. The transport term itself, already carried by GRIN1, states this correctly. Proposed replacements: calcium ion transmembrane import into cytosol Supporting Evidence: PMID:17308309 ADDLs bind to or in close proximity to NMDA-Rs, triggering neuronal damage through NMDA-R-dependent calcium flux PMID:7685113 Expressed hNR1 homomeric receptor channels exhibit the high Ca2+ permeability characteristic of neuronal NMDA receptors |
| GO:0014069 postsynaptic density | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from mouse GluN1 (PMID:15317856 and others), measured in PSD fractions. Reason: GluN1 is a core component of the postsynaptic density fraction. Supporting Evidence: PMID:15317856 The most severe deficit was observed in the postsynaptic density (PSD) fraction |
| GO:0015276 ligand-gated monoatomic ion channel activity | IBA GO_REF:0000033 | MODIFY | Summary: PAINT places this at PTN000437926, the root of the ionotropic glutamate receptor family, which is why it stops at a general term. Reason: True of GluN1 but less specific than the evidence. NMDA glutamate receptor activity is a descendant of this term and GRIN1 carries it with direct experimental support; with GluN3 partners the specific activity is glycine-gated cation channel activity, also a descendant. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000437926 Β· PANTHER:PTN000437926 SUPPORTS TRANSFER Root node of the ionotropic glutamate receptor family (plants to animals). The term is general because it has to hold for AMPA, kainate, delta, NMDA and plant GLR members alike; the inheritance is sound and GRIN1 is inside the clade. Proposed replacements: NMDA glutamate receptor activity glycine-gated cation channel activity Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt 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+) PMID:11823786 NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA |
| GO:0015276 ligand-gated monoatomic ion channel activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping from ionotropic glutamate receptor signatures. Reason: True of GluN1 but less specific than the evidence. NMDA glutamate receptor activity is a descendant of this term and GRIN1 carries it with direct experimental support; with GluN3 partners the specific activity is glycine-gated cation channel activity, also a descendant. Proposed replacements: NMDA glutamate receptor activity glycine-gated cation channel activity Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt 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+) PMID:11823786 NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA |
| GO:0015280 ligand-gated sodium channel activity | IDA PMID:21376300 Excess of de novo deleterious mutations in genes associated ... | ACCEPT | Summary: Functional testing of de novo GRIN1 missense variants in cell culture, from which UniProt records sodium conductance. Reason: NMDA receptors are non-selective cation channels that carry sodium as well as calcium, so the activity is correct for GluN1-containing receptors. It is not refined to NMDA glutamate receptor activity because that term is not a descendant of this one in GO. Only the abstract of the cited paper is cached and it does not describe the recordings, so the row rests on the curated UniProt reaction, which cites this paper, and on the known sodium permeability. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt Reaction=Na(+)(in) = Na(+)(out) PMID:26919761 The N-methyl-D-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable ionotropic glutamate receptor that is activated by the coagonists glycine and glutamate |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping. Reason: Correct but general: GluN1 is a multi-pass protein of the plasma membrane, concentrated in the postsynaptic membrane. Both descendants are already annotated with experimental support. Proposed replacements: plasma membrane postsynaptic membrane Supporting Evidence: PMID:28228639 GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface PMID:23159309 the NMDA receptor subunits GluN1, GluN2A, GluN2B, GluN2C and GluN2D are located in postsynaptic membranes of mossy fibre as well as CA3 recurrent associational commissural synapses |
| GO:0016594 glycine binding | IDA PMID:28105280 GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive... | ACCEPT | Summary: Crystal structures of the GluN1-GluN2A ligand-binding domains were solved with glycine bound to GluN1. Reason: Binding of the co-agonist glycine is the specific molecular contribution of GluN1 to receptor gating. Supporting Evidence: PMID:28105280 The N-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca2+ and Na+ file:human/GRIN1/GRIN1-uniprot.txt The ligand-binding domain (LBD) binds to glycine (GluN1 and GluN3 subunits) and glutamate (GluN2 subunits) and control opening of the channel gate |
| GO:0016594 glycine binding | IDA PMID:7685113 Molecular cloning, functional expression, and pharmacologica... | ACCEPT | Summary: Currents from hNR1-expressing oocytes required glycine and were blocked by the glycine-site antagonist 7-chlorokynurenate. Reason: Binding of the co-agonist glycine is the specific molecular contribution of GluN1 to receptor gating. Supporting Evidence: PMID:7685113 Oocytes injected with cRNA synthesized from the hNR1 cDNA express glutamate and NMDA-activated currents in the presence of glycine file:human/GRIN1/GRIN1-uniprot.txt The ligand-binding domain (LBD) binds to glycine (GluN1 and GluN3 subunits) and glutamate (GluN2 subunits) and control opening of the channel gate |
| GO:0016594 glycine binding | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA assignment of glycine binding. Reason: GluN1 carries the glycine/D-serine co-agonist site of the NMDA receptor. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt The ligand-binding domain (LBD) binds to glycine (GluN1 and GluN3 subunits) and glutamate (GluN2 subunits) and control opening of the channel gate file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0016594 glycine binding | IMP PMID:17047094 Subunit-specific roles of glycine-binding domains in activat... | ACCEPT | Summary: Mutations in the NR1 ligand-binding core altered glycine-dependent activation and decay of NR1/NR3 receptor currents. Reason: Binding of the co-agonist glycine is the specific molecular contribution of GluN1 to receptor gating. Supporting Evidence: PMID:17047094 Agonist-bound NR1 may also contribute to peak NR1/NR3 receptor currents file:human/GRIN1/GRIN1-uniprot.txt The ligand-binding domain (LBD) binds to glycine (GluN1 and GluN3 subunits) and glutamate (GluN2 subunits) and control opening of the channel gate |
| GO:0016595 glutamate binding | IDA PMID:7685113 Molecular cloning, functional expression, and pharmacologica... | REMOVE | Summary: hNR1 cRNA injected into oocytes gave currents activated by glutamate or NMDA in the presence of glycine. Reason: The full text was read. Every experiment is two-electrode voltage clamp of oocytes injected with hNR1 cRNA alone; there is no ligand-binding assay. Glutamate sensitivity is a dose-response curve of current (EC50 3.7 uM) fitted to a binding isotherm, and the currents were small (4 to 60 nA). The paper itself notes that NR1 co-expressed with NR2 subunits gives about 100-fold larger currents. Direct evidence places glutamate on GluN2, not GluN1: the isolated GluN1 ligand-binding core does not detectably bind glutamate (PMID:16641235), its crystal structure forms the glycine/D-serine site (PMID:12805203), and in HEK293 cells, which carry no endogenous NMDA receptor subunits, GluN1 expressed alone gives no response unless a GluN2 subunit is co-expressed (PMID:16214956). The glutamate-evoked currents from GluN1-alone oocytes are therefore not from a homomeric GluN1 glutamate receptor; their origin is unresolved (the once-proposed endogenous Xenopus partner XenU1 was experimentally excluded and is a kainate-binding protein, not a GluN2 subunit). The receptor complex responds to glutamate, which the NMDA receptor activity term already records; the binding term on GluN1 itself is not supported. Supporting Evidence: PMID:16641235 binding of glutamate to NR1 was not detectable even at a 300 mm concentration PMID:16214956 In HEK293 cells, we did not get receptor response unless an NR2 subunit was coexpressed PMID:12805203 NMDA receptors require both glycine and glutamate for activation with NR1 and NR2 forming glycine and glutamate sites, respectively file:human/GRIN1/GRIN1-uniprot.txt The ligand-binding domain (LBD) binds to glycine (GluN1 and GluN3 subunits) and glutamate (GluN2 subunits) and control opening of the channel gate file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit PMID:7685113 Oocytes injected with cRNA synthesized from the hNR1 cDNA express glutamate and NMDA-activated currents in the presence of glycine file:human/GRIN1/GRIN1-hypotheses/homomeric-glun1-oocyte-currents-need-xenopus-glun2/openscientist.md |
| GO:0017146 NMDA selective glutamate receptor complex | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT places NMDA receptor complex membership at PTN001451205 (the GluN1 clade), seeded by fly, mouse, rat, Xenopus and human GluN1. Reason: GluN1 is present in every NMDA receptor tetramer; human GRIN1 has direct structural evidence of its own. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) PMID:34321660 we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate |
| GO:0017146 NMDA selective glutamate receptor complex | IDA PMID:10480938 Biochemical evidence for the co-association of three N-methy... | ACCEPT | Summary: NR1-1a co-purified with NR2A and two differently tagged NR2B subunits from transfected HEK293 cells by double immunoaffinity purification. Reason: GluN1 is the obligatory subunit of the heterotetrameric NMDA receptor. Supporting Evidence: PMID:10480938 Immunoblotting of the double immunopurified NR2A/NR2B(FLAG)-containing material demonstrated the presence of anti-NR1, anti-NR2A, anti-FLAG, and, more important, anti-c-Myc antibody immunoreactivities file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0017146 NMDA selective glutamate receptor complex | IDA PMID:17047094 Subunit-specific roles of glycine-binding domains in activat... | ACCEPT | Summary: NR1/NR3 receptors were studied by mutagenesis of the NR1 and NR3 ligand-binding cores. These are glycine-gated receptors of the NMDA receptor family, which GO and ComplexPortal place under this complex term. Reason: GluN1 is the obligatory subunit of the heterotetrameric NMDA receptor. Supporting Evidence: PMID:17047094 N-Methyl-D-aspartate receptors (NMDARs) composed of NR1 and NR3 subunits differ from other NMDAR subtypes in that they require glycine alone for activation file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0017146 NMDA selective glutamate receptor complex | IDA PMID:26875626 Positive Allosteric Modulators of GluN2A-Containing NMDARs w... | ACCEPT | Summary: Crystal structures of the GluN1-GluN2A ligand-binding-domain heterodimer with bound modulators. Reason: GluN1 is the obligatory subunit of the heterotetrameric NMDA receptor. Supporting Evidence: PMID:26875626 Potentiation was observed with recombinant triheteromeric GluN1/GluN2A/GluN2B NMDARs and with synaptically activated NMDARs in brain slices file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0017146 NMDA selective glutamate receptor complex | IDA PMID:26919761 Discovery of GluN2A-Selective NMDA Receptor Positive Alloste... | ACCEPT | Summary: Crystallography and electrophysiology of GluN1/GluN2A with GluN2A-selective modulators. Reason: GluN1 is the obligatory subunit of the heterotetrameric NMDA receptor. Supporting Evidence: PMID:26919761 The N-methyl-D-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable ionotropic glutamate receptor that is activated by the coagonists glycine and glutamate file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0017146 NMDA selective glutamate receptor complex | IDA PMID:28105280 GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive... | ACCEPT | Summary: X-ray structures of the GluN1-GluN2A ligand-binding domains with a modulator bound at the subunit interface. Reason: GluN1 is the obligatory subunit of the heterotetrameric NMDA receptor. Supporting Evidence: PMID:28105280 The N-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca2+ and Na+ file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0017146 NMDA selective glutamate receptor complex | IDA PMID:28126851 Functional Evaluation of a De Novo GRIN2A Mutation Identifie... | ACCEPT | Summary: Functional GluN1/GluN2A receptors were assembled from human subunits. Reason: GluN1 is the obligatory subunit of the heterotetrameric NMDA receptor. Supporting Evidence: PMID:28126851 the mutant GluN2A(M817V)-containing receptors showed enhanced agonist potency, reduced sensitivity to endogenous negative inhibitors (Mg2+, proton, and zinc) file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0017146 NMDA selective glutamate receptor complex | IDA PMID:36309015 Structural insights into assembly and function of GluN1-2C, ... | ACCEPT | Summary: Cryo-EM structures of human GluN1-2C, GluN1-2A-2C and GluN1-2D receptors. Reason: GluN1 is the obligatory subunit of the heterotetrameric NMDA receptor. Supporting Evidence: PMID:36309015 NMDARs are glycine- and glutamate-gated ion channels that exist as heterotetramers composed of obligatory GluN1 and GluN2(A-D) and/or GluN3(A-B) file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0017146 NMDA selective glutamate receptor complex | IDA PMID:36959261 Distinct structure and gating mechanism in diverse NMDA rece... | ACCEPT | Summary: Cryo-EM structure of the human GluN1-GluN2D di-heterotetramer. Reason: GluN1 is the obligatory subunit of the heterotetrameric NMDA receptor. Supporting Evidence: PMID:36959261 N-methyl-D-aspartate (NMDA) receptors are heterotetramers comprising two GluN1 and two alternate GluN2 (N2A-N2D) subunits file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0017146 NMDA selective glutamate receptor complex | IDA PMID:7679115 Molecular cloning and chromosomal localization of the key su... | ACCEPT | Summary: Human NMDAR1 produced functional NMDA receptor channels in oocytes. Reason: GluN1 is the obligatory subunit of the heterotetrameric NMDA receptor. Supporting Evidence: PMID:7679115 Expression in Xenopus oocytes demonstrated that the single protein encoded by the cloned cDNA possesses the electrophysiological and pharmacological properties characteristic of the NMDA receptor, including Ca2+ permeability, voltage-dependent Mg2+ block, and inhibition by selective antagonists such as Zn2+ and channel blockers file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0017146 NMDA selective glutamate receptor complex | IEA GO_REF:0000117 | ACCEPT | Summary: Complex membership transferred electronically or from the rat GluN1 record and the GluN1-GluN2A ComplexPortal entry. Reason: Consistent with the cryo-EM structures of human GluN1-GluN2 receptors. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) PMID:34321660 we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate |
| GO:0017146 NMDA selective glutamate receptor complex | IPI PMID:34321660 Structural basis of ketamine action on human NMDA receptors. | ACCEPT | Summary: Cryo-EM structures of human GluN1-GluN2A and GluN1-GluN2B receptors with S-ketamine. Reason: GluN1 is the obligatory subunit of the heterotetrameric NMDA receptor. Supporting Evidence: PMID:34321660 we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0017146 NMDA selective glutamate receptor complex | IPI PMID:36309015 Structural insights into assembly and function of GluN1-2C, ... | ACCEPT | Summary: Cryo-EM structures of human GluN1-2C, GluN1-2A-2C and GluN1-2D receptors. Reason: GluN1 is the obligatory subunit of the heterotetrameric NMDA receptor. Supporting Evidence: PMID:36309015 NMDARs are glycine- and glutamate-gated ion channels that exist as heterotetramers composed of obligatory GluN1 and GluN2(A-D) and/or GluN3(A-B) file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0017146 NMDA selective glutamate receptor complex | ISS GO_REF:0000024 | ACCEPT | Summary: Complex membership transferred electronically or from the rat GluN1 record and the GluN1-GluN2A ComplexPortal entry. Reason: Consistent with the cryo-EM structures of human GluN1-GluN2 receptors. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) PMID:34321660 we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate |
| GO:0017146 NMDA selective glutamate receptor complex | ISS GO_REF:0000114 | ACCEPT | Summary: Complex membership transferred electronically or from the rat GluN1 record and the GluN1-GluN2A ComplexPortal entry. Reason: Consistent with the cryo-EM structures of human GluN1-GluN2 receptors. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) PMID:34321660 we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate |
| GO:0017146 NMDA selective glutamate receptor complex | TAS PMID:17526495 Fyn-mediated phosphorylation of NR2B Tyr-1336 controls calpa... | ACCEPT | Summary: TAS statement from a study of NR1/NR2B receptors. Reason: GluN1 is the obligatory subunit of the heterotetrameric NMDA receptor. Supporting Evidence: PMID:17526495 truncated NR1/2B receptors similar to those generated by calpain have electrophysiological properties matching those of wild-type receptors file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0018964 propylene metabolic process | ISS GO_REF:0000024 | REMOVE | Summary: Transferred from a mouse GluN1 annotation citing PMID:21795692, a study of Shank3 knockdown and mGluR5 signalling in neuronal cultures. Reason: GluN1 is an ion channel subunit with no enzymatic role, and the cited paper does not mention propylene or any hydrocarbon metabolism (full text searched). The donor term looks like a data-entry error, and the transfer to human should not stand. Supporting Evidence: PMID:21795692 this treatment specifically reduced the synaptic expression of the metabotropic glutamate receptor 5 (mGluR5), but did not affect the expression of other major synaptic proteins file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0019722 calcium-mediated signaling | IEA GO_REF:0000108 | ACCEPT | Summary: Inferred automatically from glutamate-gated calcium channel activity. Reason: Calcium entering through the NMDA receptor is the second messenger that couples synaptic activity to downstream pathways; the channel generates that signal. Supporting Evidence: Reactome:R-HSA-432164 The local rise in the Ca2+ ion concentration further leads to activation of several Ca2+ dependent pathways file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0022824 transmitter-gated monoatomic ion channel activity | ISS GO_REF:0000024 | MODIFY | Summary: Transferred from rat GluN1 (PMID:11823786). Reason: The donor paper shows two specific transmitter-gated activities for NR1: the conventional glutamate/glycine-gated NMDA receptor and the glycine-gated NR1/NR3 channel. Both are descendants of this term and both are already annotated to GRIN1. Proposed replacements: NMDA glutamate receptor activity glycine-gated cation channel activity Supporting Evidence: PMID:11823786 NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA |
| GO:0022824 transmitter-gated monoatomic ion channel activity | ISS GO_REF:0000024 | MODIFY | Summary: Transferred from a rat GluN3 subunit (Grin3a or Grin3b), with which NR1 forms a receptor. Reason: The receptor formed with GluN3 subunits is a glycine-gated cation channel; that descendant term is the specific statement and GRIN1 already carries it. Proposed replacements: glycine-gated cation channel activity Supporting Evidence: PMID:11823786 NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA PMID:38598639 Uniquely, NMDARs composed of GluN1 and GluN3 are activated exclusively by glycine |
| GO:0022824 transmitter-gated monoatomic ion channel activity | ISS GO_REF:0000024 | MODIFY | Summary: Transferred from a rat GluN3 subunit (Grin3a or Grin3b), with which NR1 forms a receptor. Reason: The receptor formed with GluN3 subunits is a glycine-gated cation channel; that descendant term is the specific statement and GRIN1 already carries it. Proposed replacements: glycine-gated cation channel activity Supporting Evidence: PMID:11823786 NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA PMID:38598639 Uniquely, NMDARs composed of GluN1 and GluN3 are activated exclusively by glycine |
| GO:0022849 glutamate-gated calcium ion channel activity | IDA PMID:28126851 Functional Evaluation of a De Novo GRIN2A Mutation Identifie... | ACCEPT | Summary: Glutamate-gated, calcium-permeable currents were recorded from receptors containing human GluN1. Reason: Describes the calcium-conducting activity of the NMDA receptor accurately; GluN1 contributes pore-lining segments. Supporting Evidence: PMID:28126851 the mutant GluN2A(M817V)-containing receptors showed enhanced agonist potency, reduced sensitivity to endogenous negative inhibitors (Mg2+, proton, and zinc) file:human/GRIN1/GRIN1-uniprot.txt The transmembrane domain (TMD) harbors the channel gate and pore |
| GO:0022849 glutamate-gated calcium ion channel activity | IDA PMID:7679115 Molecular cloning and chromosomal localization of the key su... | ACCEPT | Summary: Glutamate-gated, calcium-permeable currents were recorded from receptors containing human GluN1. Reason: Describes the calcium-conducting activity of the NMDA receptor accurately; GluN1 contributes pore-lining segments. Supporting Evidence: PMID:7679115 Expression in Xenopus oocytes demonstrated that the single protein encoded by the cloned cDNA possesses the electrophysiological and pharmacological properties characteristic of the NMDA receptor, including Ca2+ permeability, voltage-dependent Mg2+ block, and inhibition by selective antagonists such as Zn2+ and channel blockers file:human/GRIN1/GRIN1-uniprot.txt The transmembrane domain (TMD) harbors the channel gate and pore |
| GO:0030425 dendrite | IDA PMID:10749211 NMDA spikes in basal dendrites of cortical pyramidal neurons... | ACCEPT | Summary: NMDA receptor channels in basal dendrites of cortical pyramidal neurons generated local dendritic spikes. Reason: Dendrites are the main site of NMDA receptor function. The cached abstract does not state the species studied; the localisation itself is well supported for GluN1. Supporting Evidence: PMID:10749211 these spikes were mediated mostly by NMDA (N-methyl-D-aspartate) receptor channels, which contributed at least 80% of the total charge PMID:17207780 A high percentage of thalamo-amygdaloid spines was immunoreactive for GluR2 (80%), GluR3 (83%), and NR1 (83%) |
| GO:0030425 dendrite | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA assignment of dendrite localisation. Reason: NMDA receptors are concentrated on dendrites and dendritic spines. Supporting Evidence: PMID:10749211 these spikes were mediated mostly by NMDA (N-methyl-D-aspartate) receptor channels, which contributed at least 80% of the total charge PMID:17207780 A high percentage of thalamo-amygdaloid spines was immunoreactive for GluR2 (80%), GluR3 (83%), and NR1 (83%) |
| GO:0035235 ionotropic glutamate receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT places this pathway at PTN001451205, the GluN1 clade. Reason: GluN1 is a subunit of the ionotropic glutamate receptor that initiates the pathway. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt 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+) file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0035235 ionotropic glutamate receptor signaling pathway | IMP PMID:28228639 GRIN1 mutation associated with intellectual disability alter... | ACCEPT | Summary: A GRIN1 pore variant reduced receptor surface delivery and current responses. Reason: GluN1 is an obligatory subunit of the receptor that transduces the glutamate signal. Supporting Evidence: PMID:28228639 GluN1-G620R/GluN2A complexes showed a mild reduction in trafficking, a ~2-fold decrease in glutamate and glycine potency, a strong decrease in sensitivity to Mg2+ block file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0035235 ionotropic glutamate receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from mouse GluN1 or from the GluN1-GluN2A complex entry. Reason: Signalling by glutamate through the NMDA receptor requires GluN1. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit PMID:8980238 Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning |
| GO:0035235 ionotropic glutamate receptor signaling pathway | ISS GO_REF:0000114 | ACCEPT | Summary: Transferred from mouse GluN1 or from the GluN1-GluN2A complex entry. Reason: Signalling by glutamate through the NMDA receptor requires GluN1. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit PMID:8980238 Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning |
| GO:0035235 ionotropic glutamate receptor signaling pathway | NAS PMID:34321660 Structural basis of ketamine action on human NMDA receptors. | ACCEPT | Summary: Author statement accompanying a structural study of human GluN1-containing receptors. Reason: GluN1 is an obligatory subunit of the receptor that transduces the glutamate signal. Supporting Evidence: PMID:34321660 we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0035235 ionotropic glutamate receptor signaling pathway | NAS PMID:36309015 Structural insights into assembly and function of GluN1-2C, ... | ACCEPT | Summary: Author statement accompanying a structural study of human GluN1-containing receptors. Reason: GluN1 is an obligatory subunit of the receptor that transduces the glutamate signal. Supporting Evidence: PMID:36309015 NMDARs are glycine- and glutamate-gated ion channels that exist as heterotetramers composed of obligatory GluN1 and GluN2(A-D) and/or GluN3(A-B) file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0035235 ionotropic glutamate receptor signaling pathway | NAS PMID:36959261 Distinct structure and gating mechanism in diverse NMDA rece... | ACCEPT | Summary: Author statement accompanying a structural study of human GluN1-containing receptors. Reason: GluN1 is an obligatory subunit of the receptor that transduces the glutamate signal. Supporting Evidence: PMID:36959261 N-methyl-D-aspartate (NMDA) receptors are heterotetramers comprising two GluN1 and two alternate GluN2 (N2A-N2D) subunits file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:0035725 sodium ion transmembrane transport | IDA PMID:7679115 Molecular cloning and chromosomal localization of the key su... | ACCEPT | Summary: Currents through human NMDAR1 channels in oocytes. Reason: Sodium is a major charge carrier of the NMDA receptor current. Supporting Evidence: PMID:7679115 Expression in Xenopus oocytes demonstrated that the single protein encoded by the cloned cDNA possesses the electrophysiological and pharmacological properties characteristic of the NMDA receptor, including Ca2+ permeability, voltage-dependent Mg2+ block, and inhibition by selective antagonists such as Zn2+ and channel blockers PMID:26919761 The N-methyl-D-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable ionotropic glutamate receptor that is activated by the coagonists glycine and glutamate |
| GO:0038023 signaling receptor activity | IBA GO_REF:0000033 | MODIFY | Summary: PAINT places this at PTN000437926, the root of the ionotropic glutamate receptor family, which is why it stops at a general term. Reason: True of GluN1 but less specific than the evidence. NMDA glutamate receptor activity is a descendant of this term and GRIN1 carries it with direct experimental support; with GluN3 partners the specific activity is glycine-gated cation channel activity, also a descendant. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000437926 Β· PANTHER:PTN000437926 SUPPORTS TRANSFER Root node of the ionotropic glutamate receptor family (plants to animals). The term is general because it has to hold for AMPA, kainate, delta, NMDA and plant GLR members alike; the inheritance is sound and GRIN1 is inside the clade. Proposed replacements: NMDA glutamate receptor activity glycine-gated cation channel activity Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt 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+) PMID:11823786 NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA |
| GO:0038023 signaling receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO mapping from ionotropic glutamate receptor signatures. Reason: True of GluN1 but less specific than the evidence. NMDA glutamate receptor activity is a descendant of this term and GRIN1 carries it with direct experimental support; with GluN3 partners the specific activity is glycine-gated cation channel activity, also a descendant. Proposed replacements: NMDA glutamate receptor activity glycine-gated cation channel activity Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt 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+) PMID:11823786 NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA |
| GO:0042391 regulation of membrane potential | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT annotation at PTN001451205 (GluN1 clade). Reason: Opening of the NMDA receptor passes cation current that depolarises the membrane. Supporting Evidence: PMID:7679115 Expression in Xenopus oocytes demonstrated that the single protein encoded by the cloned cDNA possesses the electrophysiological and pharmacological properties characteristic of the NMDA receptor, including Ca2+ permeability, voltage-dependent Mg2+ block, and inhibition by selective antagonists such as Zn2+ and channel blockers file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0042391 regulation of membrane potential | IDA PMID:17047094 Subunit-specific roles of glycine-binding domains in activat... | ACCEPT | Summary: Agonist-evoked currents through receptors containing human GluN1 were recorded in heterologous cells. Reason: Cation current through the receptor changes membrane potential. The recordings were made in oocytes or HEK cells, so the general term is as specific as this evidence allows; the synaptic form is annotated separately. Supporting Evidence: PMID:17047094 N-Methyl-D-aspartate receptors (NMDARs) composed of NR1 and NR3 subunits differ from other NMDAR subtypes in that they require glycine alone for activation file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0042391 regulation of membrane potential | IDA PMID:7679115 Molecular cloning and chromosomal localization of the key su... | ACCEPT | Summary: Agonist-evoked currents through receptors containing human GluN1 were recorded in heterologous cells. Reason: Cation current through the receptor changes membrane potential. The recordings were made in oocytes or HEK cells, so the general term is as specific as this evidence allows; the synaptic form is annotated separately. Supporting Evidence: PMID:7679115 Expression in Xenopus oocytes demonstrated that the single protein encoded by the cloned cDNA possesses the electrophysiological and pharmacological properties characteristic of the NMDA receptor, including Ca2+ permeability, voltage-dependent Mg2+ block, and inhibition by selective antagonists such as Zn2+ and channel blockers file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0042391 regulation of membrane potential | IDA PMID:7685113 Molecular cloning, functional expression, and pharmacologica... | ACCEPT | Summary: Agonist-evoked currents through receptors containing human GluN1 were recorded in heterologous cells. Reason: Cation current through the receptor changes membrane potential. The recordings were made in oocytes or HEK cells, so the general term is as specific as this evidence allows; the synaptic form is annotated separately. Supporting Evidence: PMID:7685113 Oocytes injected with cRNA synthesized from the hNR1 cDNA express glutamate and NMDA-activated currents in the presence of glycine file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0042391 regulation of membrane potential | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA assignment. Reason: Opening of the NMDA receptor passes cation current that depolarises the membrane. Supporting Evidence: PMID:7679115 Expression in Xenopus oocytes demonstrated that the single protein encoded by the cloned cDNA possesses the electrophysiological and pharmacological properties characteristic of the NMDA receptor, including Ca2+ permeability, voltage-dependent Mg2+ block, and inhibition by selective antagonists such as Zn2+ and channel blockers file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0042734 presynaptic membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from rat GluN1 (PMID:19666514) or from mouse GluN3B. Reason: Presynaptic NMDA receptors exist at some synapses, and immunogold EM places GluN1 in presynaptic terminal membranes. This is a minor pool beside the postsynaptic one. Supporting Evidence: PMID:23159309 these subunits were located also presynaptically in nerve terminal membranes and in mossy fibre axons PMID:19666514 there is also accumulating evidence for the existence of presynaptic NMDA receptors in several brain structures |
| GO:0042734 presynaptic membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from rat GluN1 (PMID:19666514) or from mouse GluN3B. Reason: Presynaptic NMDA receptors exist at some synapses, and immunogold EM places GluN1 in presynaptic terminal membranes. This is a minor pool beside the postsynaptic one. Supporting Evidence: PMID:23159309 these subunits were located also presynaptically in nerve terminal membranes and in mossy fibre axons PMID:19666514 there is also accumulating evidence for the existence of presynaptic NMDA receptors in several brain structures |
| GO:0043005 neuron projection | IBA GO_REF:0000033 | MODIFY | Summary: PAINT annotation at PTN001451205 (GluN1 clade). Reason: Correct but general. The neuron projections in which GluN1 is found are dendrites and their spines; both are descendants already annotated to GRIN1. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001451205 Β· PANTHER:PTN001451205 SUPPORTS TRANSFER GluN1 clade node seeded by fly Nmdar1, mouse Grin1 and rat Grin1. The node placement is sound; the term is simply broader than what is established for GluN1, and the specific descendant is already annotated. Proposed replacements: dendrite dendritic spine Supporting Evidence: PMID:17207780 A high percentage of thalamo-amygdaloid spines was immunoreactive for GluR2 (80%), GluR3 (83%), and NR1 (83%) PMID:10749211 these spikes were mediated mostly by NMDA (N-methyl-D-aspartate) receptor channels, which contributed at least 80% of the total charge |
| GO:0043005 neuron projection | ISS GO_REF:0000024 | MODIFY | Summary: Transferred from mouse GluN1. Reason: Correct but general. The neuron projections in which GluN1 is found are dendrites and their spines; both are descendants already annotated to GRIN1. Proposed replacements: dendrite dendritic spine Supporting Evidence: PMID:17207780 A high percentage of thalamo-amygdaloid spines was immunoreactive for GluR2 (80%), GluR3 (83%), and NR1 (83%) PMID:10749211 these spikes were mediated mostly by NMDA (N-methyl-D-aspartate) receptor channels, which contributed at least 80% of the total charge |
| GO:0043083 synaptic cleft | ISS GO_REF:0000024 | MODIFY | Summary: Transferred from rat GluN1 (PMID:17207780), an immunogold EM study of spine synapses. Reason: GluN1 is an integral membrane protein. Gold particles over the cleft mark its extracellular domains, which are anchored in the postsynaptic membrane; that is the accurate location term. Proposed replacements: postsynaptic membrane Supporting Evidence: PMID:17207780 A high percentage of thalamo-amygdaloid spines was immunoreactive for GluR2 (80%), GluR3 (83%), and NR1 (83%) PMID:23159309 the NMDA receptor subunits GluN1, GluN2A, GluN2B, GluN2C and GluN2D are located in postsynaptic membranes of mossy fibre as well as CA3 recurrent associational commissural synapses |
| GO:0043195 terminal bouton | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from rat GluN1 (PMID:19666514), a study of presynaptic NMDA receptors at cerebellar parallel fibre synapses. Reason: Consistent with a presynaptic receptor pool at some synapses; not the main site of action. Supporting Evidence: PMID:19666514 there is also accumulating evidence for the existence of presynaptic NMDA receptors in several brain structures PMID:23159309 these subunits were located also presynaptically in nerve terminal membranes and in mossy fibre axons |
| GO:0043197 dendritic spine | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from rat GluN1 (PMID:17207780), where immunogold EM found NR1 in 83% of thalamo-amygdaloid spines. Reason: Dendritic spines carry the excitatory postsynaptic sites where NMDA receptors act. Supporting Evidence: PMID:17207780 A high percentage of thalamo-amygdaloid spines was immunoreactive for GluR2 (80%), GluR3 (83%), and NR1 (83%) |
| GO:0044877 protein-containing complex binding | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Transferred from rat GluN1; donors are the amyloid-beta oligomer co-immunoprecipitation (PMID:17308309) and structural studies of subunit arrangement. Reason: An uninformative binding term. Where it reflects assembly with other receptor subunits, the complex term already says so; where it reflects amyloid-beta oligomers, the donor shows only proximity. Supporting Evidence: PMID:17308309 ADDLs bind to or in close proximity to NMDA-Rs, triggering neuronal damage through NMDA-R-dependent calcium flux file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0045202 synapse | IBA GO_REF:0000033 | MODIFY | Summary: PAINT annotation at PTN001451205 (GluN1 clade). Reason: Correct but general. Immunogold EM places GluN1 in the postsynaptic membrane, a part of the synapse that GRIN1 is already annotated to. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001451205 Β· PANTHER:PTN001451205 SUPPORTS TRANSFER GluN1 clade node seeded by fly Nmdar1, mouse Grin1 and rat Grin1. The node placement is sound; the term is simply broader than what is established for GluN1, and the specific descendant is already annotated. Proposed replacements: postsynaptic membrane Supporting Evidence: PMID:23159309 the NMDA receptor subunits GluN1, GluN2A, GluN2B, GluN2C and GluN2D are located in postsynaptic membranes of mossy fibre as well as CA3 recurrent associational commissural synapses PMID:15317856 the GluRzeta1 subunit, by itself, is virtually unable to accumulate at postsynaptic sites, regardless of C-terminal forms |
| GO:0045202 synapse | ISS GO_REF:0000024 | MODIFY | Summary: Transferred from mouse GluN1. Reason: Correct but general. Immunogold EM places GluN1 in the postsynaptic membrane, a part of the synapse that GRIN1 is already annotated to. Proposed replacements: postsynaptic membrane Supporting Evidence: PMID:23159309 the NMDA receptor subunits GluN1, GluN2A, GluN2B, GluN2C and GluN2D are located in postsynaptic membranes of mossy fibre as well as CA3 recurrent associational commissural synapses PMID:15317856 the GluRzeta1 subunit, by itself, is virtually unable to accumulate at postsynaptic sites, regardless of C-terminal forms |
| GO:0045211 postsynaptic membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping. Reason: Postsynaptic membrane localisation of GluN1 is shown by immunogold EM in rodents and depends on GluN2 subunits. Supporting Evidence: PMID:23159309 the NMDA receptor subunits GluN1, GluN2A, GluN2B, GluN2C and GluN2D are located in postsynaptic membranes of mossy fibre as well as CA3 recurrent associational commissural synapses PMID:15317856 the GluRzeta1 subunit, by itself, is virtually unable to accumulate at postsynaptic sites, regardless of C-terminal forms |
| GO:0045211 postsynaptic membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from rodent GluN1. Reason: Postsynaptic membrane localisation of GluN1 is shown by immunogold EM in rodents and depends on GluN2 subunits. Supporting Evidence: PMID:23159309 the NMDA receptor subunits GluN1, GluN2A, GluN2B, GluN2C and GluN2D are located in postsynaptic membranes of mossy fibre as well as CA3 recurrent associational commissural synapses PMID:15317856 the GluRzeta1 subunit, by itself, is virtually unable to accumulate at postsynaptic sites, regardless of C-terminal forms |
| GO:0045211 postsynaptic membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from rodent GluN1. Reason: Postsynaptic membrane localisation of GluN1 is shown by immunogold EM in rodents and depends on GluN2 subunits. Supporting Evidence: PMID:23159309 the NMDA receptor subunits GluN1, GluN2A, GluN2B, GluN2C and GluN2D are located in postsynaptic membranes of mossy fibre as well as CA3 recurrent associational commissural synapses PMID:15317856 the GluRzeta1 subunit, by itself, is virtually unable to accumulate at postsynaptic sites, regardless of C-terminal forms |
| GO:0045211 postsynaptic membrane | NAS PMID:15317856 NMDA receptor GluRepsilon/NR2 subunits are essential for pos... | ACCEPT | Summary: Author statement citing the mouse study in which NR2 subunits were needed for postsynaptic accumulation of NR1. Reason: The postsynaptic membrane is where GluN1-containing receptors act. Supporting Evidence: PMID:15317856 the GluRzeta1 subunit, by itself, is virtually unable to accumulate at postsynaptic sites, regardless of C-terminal forms PMID:23159309 the NMDA receptor subunits GluN1, GluN2A, GluN2B, GluN2C and GluN2D are located in postsynaptic membranes of mossy fibre as well as CA3 recurrent associational commissural synapses |
| GO:0045471 response to ethanol | IDA PMID:18445116 Enhanced ethanol inhibition of recombinant N-methyl-D-aspart... | MARK AS OVER ANNOTATED | Summary: Ethanol inhibited glutamate-evoked currents of recombinant NMDA receptors in HEK293 cells. Reason: The result shows that the receptor is a pharmacological target of ethanol. That is an effect of a drug on the channel, not evidence that GluN1 takes part in a cellular response to ethanol. Supporting Evidence: PMID:18445116 In magnesium-free recording solution, ethanol inhibited glutamate-mediated currents in cells transfected with NMDA receptor subunits |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Transferred from mouse GluN1 (PMID:7907365): NMDA receptor activation increased transcription of the POU gene Cns-1 in cerebellar cultures. Reason: A transcriptional change downstream of pharmacological receptor activation. GluN1 is an ion channel subunit and takes no part in the transcription machinery; the effect is an indirect consequence of calcium influx. Supporting Evidence: PMID:7907365 Treatment of these cultured cells with NMDA results in an increase in the level of Cns-1 RNA PMID:7907365 calcium entry through the NMDA channel may be required for this response |
| GO:0048167 regulation of synaptic plasticity | ISS GO_REF:0000024 | ACCEPT | Summary: Statement from, or transfer of mouse annotations based on, conditional NR1 knockout studies. Reason: The NMDA receptor is the coincidence detector that induces long-term changes in synaptic strength, and deletion of the GluN1 gene removes them. Supporting Evidence: PMID:8980238 Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning PMID:15003177 our study reveals a hitherto unrecognized role of the NMDA receptor in dynamically maintaining the long-term synaptic stability of memory storage circuits in the brain |
| GO:0048167 regulation of synaptic plasticity | NAS PMID:17526495 Fyn-mediated phosphorylation of NR2B Tyr-1336 controls calpa... | ACCEPT | Summary: Statement from, or transfer of mouse annotations based on, conditional NR1 knockout studies. Reason: The NMDA receptor is the coincidence detector that induces long-term changes in synaptic strength, and deletion of the GluN1 gene removes them. Supporting Evidence: PMID:8980238 Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning PMID:15003177 our study reveals a hitherto unrecognized role of the NMDA receptor in dynamically maintaining the long-term synaptic stability of memory storage circuits in the brain |
| GO:0048168 regulation of neuronal synaptic plasticity | NAS PMID:15003177 Inducible and reversible NR1 knockout reveals crucial role o... | ACCEPT | Summary: Statement from, or transfer of mouse annotations based on, conditional NR1 knockout studies. Reason: The NMDA receptor is the coincidence detector that induces long-term changes in synaptic strength, and deletion of the GluN1 gene removes them. Supporting Evidence: PMID:8980238 Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning PMID:15003177 our study reveals a hitherto unrecognized role of the NMDA receptor in dynamically maintaining the long-term synaptic stability of memory storage circuits in the brain |
| GO:0051290 protein heterotetramerization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Transferred from rat GluN1 (PMID:24876489), the crystal structure of the heterotetrameric GluN1-GluN2B receptor. Reason: GluN1 assembles with GluN2 or GluN3 subunits into heterotetramers. This is how the receptor is built, not what it does, so it is kept as non-core. Supporting Evidence: PMID:24876489 we show the crystal structure of the intact heterotetrameric GluN1-GluN2B NMDA receptor ion channel at 4 angstroms file:human/GRIN1/GRIN1-uniprot.txt Forms heterotetrameric channels composed of two GluN1/zeta subunits (GRIN1), and two identical GluN2/epsilon subunits (GRIN2A, GRIN2B, GRIN2C or GRIN2D) or GluN3 subunits (GRIN3A or GRIN3B) |
| GO:0051968 positive regulation of synaptic transmission, glutamatergic | ISS GO_REF:0000114 | ACCEPT | Summary: Author statements and a complex-level transfer describing NMDA receptor-dependent strengthening of glutamatergic transmission. Reason: Calcium entry through GluN1-containing receptors is the trigger for long-term potentiation of glutamatergic synapses; CA1-specific deletion of the mouse gene abolishes it. Supporting Evidence: PMID:8980238 Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning file:human/GRIN1/GRIN1-uniprot.txt NMDARs participate in synaptic plasticity for learning and memory formation by contributing to the long-term potentiation (LTP) |
| GO:0051968 positive regulation of synaptic transmission, glutamatergic | NAS PMID:15003177 Inducible and reversible NR1 knockout reveals crucial role o... | ACCEPT | Summary: Author statements and a complex-level transfer describing NMDA receptor-dependent strengthening of glutamatergic transmission. Reason: Calcium entry through GluN1-containing receptors is the trigger for long-term potentiation of glutamatergic synapses; CA1-specific deletion of the mouse gene abolishes it. Supporting Evidence: PMID:8980238 Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning file:human/GRIN1/GRIN1-uniprot.txt NMDARs participate in synaptic plasticity for learning and memory formation by contributing to the long-term potentiation (LTP) |
| GO:0051968 positive regulation of synaptic transmission, glutamatergic | NAS PMID:36309015 Structural insights into assembly and function of GluN1-2C, ... | ACCEPT | Summary: Author statements and a complex-level transfer describing NMDA receptor-dependent strengthening of glutamatergic transmission. Reason: Calcium entry through GluN1-containing receptors is the trigger for long-term potentiation of glutamatergic synapses; CA1-specific deletion of the mouse gene abolishes it. Supporting Evidence: PMID:8980238 Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning file:human/GRIN1/GRIN1-uniprot.txt NMDARs participate in synaptic plasticity for learning and memory formation by contributing to the long-term potentiation (LTP) |
| GO:0055074 calcium ion homeostasis | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Transferred from mouse GluN1 (PMID:7907365), where NMDA treatment of cerebellar cultures raised Cns-1 mRNA in a calcium-dependent way. Reason: The donor shows calcium entry through the NMDA channel acting as a signal. That is calcium import and signalling, already captured by other terms, not maintenance of cellular calcium levels. Supporting Evidence: PMID:7907365 calcium entry through the NMDA channel may be required for this response |
| GO:0060076 excitatory synapse | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from rat GluN1, used as an excitatory synapse marker. Reason: GluN1 is found at glutamatergic postsynaptic sites. Supporting Evidence: PMID:23159309 the NMDA receptor subunits GluN1, GluN2A, GluN2B, GluN2C and GluN2D are located in postsynaptic membranes of mossy fibre as well as CA3 recurrent associational commissural synapses PMID:15317856 The most severe deficit was observed in the postsynaptic density (PSD) fraction |
| GO:0060079 excitatory postsynaptic potential | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from mouse GluN1 (PMID:15003177, PMID:14645471), where loss or modification of NMDA receptor subunits altered synaptic responses. Reason: Current through GluN1-containing receptors forms part of the excitatory postsynaptic potential. Supporting Evidence: PMID:8980238 Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning PMID:14645471 different NMDAR subtypes with distinct functionality assemble from NR1 with NR2A and/or NR2B subunits |
| GO:0070588 calcium ion transmembrane transport | IDA PMID:26919761 Discovery of GluN2A-Selective NMDA Receptor Positive Alloste... | ACCEPT | Summary: GluN1-containing channels studied in this paper conduct calcium. Reason: High calcium permeability is a defining property of NMDA receptors and was shown with the human subunit. Supporting Evidence: PMID:26919761 The N-methyl-D-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable ionotropic glutamate receptor that is activated by the coagonists glycine and glutamate file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0070588 calcium ion transmembrane transport | IDA PMID:28126851 Functional Evaluation of a De Novo GRIN2A Mutation Identifie... | ACCEPT | Summary: GluN1-containing channels studied in this paper conduct calcium. Reason: High calcium permeability is a defining property of NMDA receptors and was shown with the human subunit. Supporting Evidence: PMID:28126851 the mutant GluN2A(M817V)-containing receptors showed enhanced agonist potency, reduced sensitivity to endogenous negative inhibitors (Mg2+, proton, and zinc) file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0070588 calcium ion transmembrane transport | IDA PMID:7679115 Molecular cloning and chromosomal localization of the key su... | ACCEPT | Summary: GluN1-containing channels studied in this paper conduct calcium. Reason: High calcium permeability is a defining property of NMDA receptors and was shown with the human subunit. Supporting Evidence: PMID:7679115 Expression in Xenopus oocytes demonstrated that the single protein encoded by the cloned cDNA possesses the electrophysiological and pharmacological properties characteristic of the NMDA receptor, including Ca2+ permeability, voltage-dependent Mg2+ block, and inhibition by selective antagonists such as Zn2+ and channel blockers file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0070588 calcium ion transmembrane transport | IDA PMID:7681588 Inducible expression of neuronal glutamate receptor channels... | ACCEPT | Summary: GluN1-containing channels studied in this paper conduct calcium. Reason: High calcium permeability is a defining property of NMDA receptors and was shown with the human subunit. Supporting Evidence: PMID:7681588 cells from the human teratocarcinoma line NT2 are induced by retinoic acid to express neuronal N-methyl-D-aspartate (NMDA) and non-NMDA GluR channels file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0070588 calcium ion transmembrane transport | IDA PMID:7685113 Molecular cloning, functional expression, and pharmacologica... | ACCEPT | Summary: GluN1-containing channels studied in this paper conduct calcium. Reason: High calcium permeability is a defining property of NMDA receptors and was shown with the human subunit. Supporting Evidence: PMID:7685113 Expressed hNR1 homomeric receptor channels exhibit the high Ca2+ permeability characteristic of neuronal NMDA receptors file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0070588 calcium ion transmembrane transport | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA assignment of calcium ion transmembrane transport. Reason: Matches the experimentally shown calcium permeability of human GluN1-containing channels. Supporting Evidence: PMID:7685113 Expressed hNR1 homomeric receptor channels exhibit the high Ca2+ permeability characteristic of neuronal NMDA receptors file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0097060 synaptic membrane | IEA GO_REF:0000044 | MODIFY | Summary: UniProt subcellular-location mapping. Reason: Correct but general. The synaptic membrane pool that is established for GluN1 is postsynaptic; that descendant is already annotated. A smaller presynaptic pool is recorded separately. Proposed replacements: postsynaptic membrane Supporting Evidence: PMID:23159309 the NMDA receptor subunits GluN1, GluN2A, GluN2B, GluN2C and GluN2D are located in postsynaptic membranes of mossy fibre as well as CA3 recurrent associational commissural synapses |
| GO:0097060 synaptic membrane | ISS GO_REF:0000024 | MODIFY | Summary: Transferred from mouse GluN1. Reason: Correct but general. The synaptic membrane pool that is established for GluN1 is postsynaptic; that descendant is already annotated. A smaller presynaptic pool is recorded separately. Proposed replacements: postsynaptic membrane Supporting Evidence: PMID:23159309 the NMDA receptor subunits GluN1, GluN2A, GluN2B, GluN2C and GluN2D are located in postsynaptic membranes of mossy fibre as well as CA3 recurrent associational commissural synapses |
| GO:0097060 synaptic membrane | ISS GO_REF:0000024 | MODIFY | Summary: Transferred from rat GluN1. Reason: Correct but general. The synaptic membrane pool that is established for GluN1 is postsynaptic; that descendant is already annotated. A smaller presynaptic pool is recorded separately. Proposed replacements: postsynaptic membrane Supporting Evidence: PMID:23159309 the NMDA receptor subunits GluN1, GluN2A, GluN2B, GluN2C and GluN2D are located in postsynaptic membranes of mossy fibre as well as CA3 recurrent associational commissural synapses |
| GO:0097553 calcium ion transmembrane import into cytosol | IDA PMID:26875626 Positive Allosteric Modulators of GluN2A-Containing NMDARs w... | ACCEPT | Summary: Calcium influx through recombinant and synaptic GluN1-containing NMDA receptors was measured in the modulator study. Reason: Calcium entry into the cytosol through the open channel is the defining output of the NMDA receptor. Supporting Evidence: PMID:26875626 Potentiation was observed with recombinant triheteromeric GluN1/GluN2A/GluN2B NMDARs and with synaptically activated NMDARs in brain slices file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0098655 monoatomic cation transmembrane transport | IDA PMID:24272827 GRIN2B mutations in West syndrome and intellectual disabilit... | ACCEPT | Summary: Cation currents through receptors containing human GluN1 were recorded or, for the structural papers, stated by the authors. Reason: Cation flux through the open pore is the direct result of NMDA receptor activation. Supporting Evidence: PMID:24272827 Mutations p.Asn615Ile and p.Val618Gly cause a significantly reduced Mg(2+) block and higher Ca(2+) permeability, leading to a dramatically increased Ca(2+) influx file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0098655 monoatomic cation transmembrane transport | IDA PMID:26875626 Positive Allosteric Modulators of GluN2A-Containing NMDARs w... | ACCEPT | Summary: Cation currents through receptors containing human GluN1 were recorded or, for the structural papers, stated by the authors. Reason: Cation flux through the open pore is the direct result of NMDA receptor activation. Supporting Evidence: PMID:26875626 Potentiation was observed with recombinant triheteromeric GluN1/GluN2A/GluN2B NMDARs and with synaptically activated NMDARs in brain slices file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0098655 monoatomic cation transmembrane transport | IDA PMID:38538865 De novo GRIN variants in M3 helix associated with neurologic... | ACCEPT | Summary: Cation currents through receptors containing human GluN1 were recorded or, for the structural papers, stated by the authors. Reason: Cation flux through the open pore is the direct result of NMDA receptor activation. Supporting Evidence: PMID:38538865 we report the functional consequences of 48 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M3 transmembrane helix file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0098655 monoatomic cation transmembrane transport | IDA PMID:9489750 Functional characterization of human N-methyl-D-aspartate su... | ACCEPT | Summary: Cation currents through receptors containing human GluN1 were recorded or, for the structural papers, stated by the authors. Reason: Cation flux through the open pore is the direct result of NMDA receptor activation. Supporting Evidence: PMID:9489750 glutamate, NMDA, glycine, and D-serine were significantly more potent on hNMDAR1A/2D than on hNMDAR1A/2A or hNMDAR1A/2B file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0098655 monoatomic cation transmembrane transport | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from rat GluN1. Reason: Both GluN1/GluN2 and GluN1/GluN3 receptors are cation channels. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt 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+) PMID:11823786 NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA |
| GO:0098655 monoatomic cation transmembrane transport | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from a rat GluN3 subunit with which GluN1 forms a channel. Reason: Both GluN1/GluN2 and GluN1/GluN3 receptors are cation channels. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt 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+) PMID:11823786 NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA |
| GO:0098655 monoatomic cation transmembrane transport | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from a rat GluN3 subunit with which GluN1 forms a channel. Reason: Both GluN1/GluN2 and GluN1/GluN3 receptors are cation channels. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt 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+) PMID:11823786 NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA |
| GO:0098655 monoatomic cation transmembrane transport | ISS GO_REF:0000114 | ACCEPT | Summary: Transferred from the GluN1-GluN2A ComplexPortal entry. Reason: Both GluN1/GluN2 and GluN1/GluN3 receptors are cation channels. Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt 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+) PMID:11823786 NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA |
| GO:0098655 monoatomic cation transmembrane transport | NAS PMID:34321660 Structural basis of ketamine action on human NMDA receptors. | ACCEPT | Summary: Cation currents through receptors containing human GluN1 were recorded or, for the structural papers, stated by the authors. Reason: Cation flux through the open pore is the direct result of NMDA receptor activation. Supporting Evidence: PMID:34321660 we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0098655 monoatomic cation transmembrane transport | NAS PMID:36309015 Structural insights into assembly and function of GluN1-2C, ... | ACCEPT | Summary: Cation currents through receptors containing human GluN1 were recorded or, for the structural papers, stated by the authors. Reason: Cation flux through the open pore is the direct result of NMDA receptor activation. Supporting Evidence: PMID:36309015 NMDARs are glycine- and glutamate-gated ion channels that exist as heterotetramers composed of obligatory GluN1 and GluN2(A-D) and/or GluN3(A-B) file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0098655 monoatomic cation transmembrane transport | NAS PMID:36959261 Distinct structure and gating mechanism in diverse NMDA rece... | ACCEPT | Summary: Cation currents through receptors containing human GluN1 were recorded or, for the structural papers, stated by the authors. Reason: Cation flux through the open pore is the direct result of NMDA receptor activation. Supporting Evidence: PMID:36959261 N-methyl-D-aspartate (NMDA) receptors are heterotetramers comprising two GluN1 and two alternate GluN2 (N2A-N2D) subunits file:human/GRIN1/GRIN1-uniprot.txt 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+) |
| GO:0098839 postsynaptic density membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping. Reason: GluN1 is enriched in the postsynaptic density, where NMDA receptors are anchored by PSD-95 family scaffolds. Supporting Evidence: PMID:15317856 The most severe deficit was observed in the postsynaptic density (PSD) fraction Reactome:R-HSA-9610750 are all delivered to the plasma membrane where they are anchored to postsynaptic density regions |
| GO:0098839 postsynaptic density membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from rat GluN1. Reason: GluN1 is enriched in the postsynaptic density, where NMDA receptors are anchored by PSD-95 family scaffolds. Supporting Evidence: PMID:15317856 The most severe deficit was observed in the postsynaptic density (PSD) fraction Reactome:R-HSA-9610750 are all delivered to the plasma membrane where they are anchored to postsynaptic density regions |
| GO:0098878 neurotransmitter receptor complex | IDA PMID:38598639 Structure and function of GluN1-3A NMDA receptor excitatory ... | ACCEPT | Summary: Cryo-EM structures of the GluN1-3A receptor with glycine or CNQX bound. Reason: GluN1-GluN3A receptors are gated by glycine and do not respond to glutamate or NMDA, so the broader neurotransmitter receptor complex term is the right level for this assembly. Supporting Evidence: PMID:38598639 The structures show a 1-3-1-3 subunit heterotetrameric arrangement PMID:38598639 Uniquely, NMDARs composed of GluN1 and GluN3 are activated exclusively by glycine |
| GO:0098878 neurotransmitter receptor complex | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from mouse GluN1 (PMID:12008020), where NR3B co-immunoprecipitated with NR1a and NR2A. Reason: True, and consistent with the row for the GluN1-GluN3A receptor. Receptors that also contain GluN2 subunits are covered by the more specific NMDA receptor complex term, which GRIN1 carries. Supporting Evidence: PMID:12008020 NR3B could form NMDA receptor complex with NR1a and NR2A subunits in heterologous cells PMID:38598639 The structures show a 1-3-1-3 subunit heterotetrameric arrangement |
| GO:0098976 excitatory chemical synaptic transmission | NAS PMID:17526495 Fyn-mediated phosphorylation of NR2B Tyr-1336 controls calpa... | ACCEPT | Summary: Author statement that NMDA receptors mediate excitatory transmission. Reason: NMDA receptors carry the slow component of the excitatory postsynaptic current at glutamatergic synapses. Supporting Evidence: PMID:8980238 Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning PMID:17526495 truncated NR1/2B receptors similar to those generated by calpain have electrophysiological properties matching those of wild-type receptors |
| GO:0160212 glycine-gated cation channel activity | ISS GO_REF:0000024 | ACCEPT | Summary: Transferred from rat GluN1 (PMID:11823786): NR1 co-assembles with NR3A or NR3B to form excitatory glycine receptors. Reason: GluN1/GluN3 receptors are cation channels gated by glycine alone. The human GluN1-3A receptor has since been characterised structurally and functionally (PMID:38598639). Supporting Evidence: PMID:11823786 NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA PMID:38598639 Uniquely, NMDARs composed of GluN1 and GluN3 are activated exclusively by glycine |
| GO:1903428 positive regulation of reactive oxygen species biosynthetic process | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Transferred from rat GluN1 (PMID:17308309): amyloid-beta oligomers induced neuronal ROS formation that required NMDA receptor activation. Reason: ROS production here is a pathological downstream consequence of excessive calcium influx, not a process GluN1 carries out. Supporting Evidence: PMID:17308309 ADDLs stimulated excessive formation of reactive oxygen species (ROS) through a mechanism requiring N-methyl-d-aspartate receptor (NMDA-R) activation |
| GO:1904062 regulation of monoatomic cation transmembrane transport | ISS GO_REF:0000114 | MODIFY | Summary: Author statement or complex-level transfer describing the receptor as regulating cation flux. Reason: GluN1 is part of the channel that carries the cations; it does not regulate a separate transporter. The transport term itself is the accurate statement and GRIN1 already carries it. Proposed replacements: monoatomic cation transmembrane transport Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt 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+) file:human/GRIN1/GRIN1-uniprot.txt The transmembrane domain (TMD) harbors the channel gate and pore |
| GO:1904062 regulation of monoatomic cation transmembrane transport | NAS PMID:15003177 Inducible and reversible NR1 knockout reveals crucial role o... | MODIFY | Summary: Author statement or complex-level transfer describing the receptor as regulating cation flux. Reason: GluN1 is part of the channel that carries the cations; it does not regulate a separate transporter. The transport term itself is the accurate statement and GRIN1 already carries it. Proposed replacements: monoatomic cation transmembrane transport Supporting Evidence: file:human/GRIN1/GRIN1-uniprot.txt 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+) file:human/GRIN1/GRIN1-uniprot.txt The transmembrane domain (TMD) harbors the channel gate and pore |
| GO:1904062 regulation of monoatomic cation transmembrane transport | NAS PMID:34321660 Structural basis of ketamine action on human NMDA receptors. | MODIFY | Summary: Author statement or complex-level transfer describing the receptor as regulating cation flux. Reason: GluN1 is part of the channel that carries the cations; it does not regulate a separate transporter. The transport term itself is the accurate statement and GRIN1 already carries it. Proposed replacements: monoatomic cation transmembrane transport Supporting Evidence: PMID:34321660 we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate file:human/GRIN1/GRIN1-uniprot.txt 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+) file:human/GRIN1/GRIN1-uniprot.txt The transmembrane domain (TMD) harbors the channel gate and pore |
| GO:1904062 regulation of monoatomic cation transmembrane transport | NAS PMID:36309015 Structural insights into assembly and function of GluN1-2C, ... | MODIFY | Summary: Author statement or complex-level transfer describing the receptor as regulating cation flux. Reason: GluN1 is part of the channel that carries the cations; it does not regulate a separate transporter. The transport term itself is the accurate statement and GRIN1 already carries it. Proposed replacements: monoatomic cation transmembrane transport Supporting Evidence: PMID:36309015 NMDARs are glycine- and glutamate-gated ion channels that exist as heterotetramers composed of obligatory GluN1 and GluN2(A-D) and/or GluN3(A-B) file:human/GRIN1/GRIN1-uniprot.txt 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+) file:human/GRIN1/GRIN1-uniprot.txt The transmembrane domain (TMD) harbors the channel gate and pore |
| GO:1904646 cellular response to amyloid-beta | IGI NOT PMID:21883149 A Ξ²-amyloid oligomer directly modulates P/Q-type calcium cur... | MARK AS OVER ANNOTATED | Summary: NOT annotation: a synthetic amyloid-beta globulomer did not change glutamate-induced currents of recombinant NMDA receptors in Xenopus oocytes. Reason: The experiment is sound but narrow: one oligomer preparation, recombinant receptors, no neuronal context. Studies in neurons report NMDA receptor-dependent responses to amyloid-beta oligomers (PMID:17308309), so a general statement that GluN1 takes no part in the cellular response to amyloid-beta is broader than this result supports. Supporting Evidence: PMID:21883149 Also globulomer AΞ² had no effect on glutamate-induced NMDA currents PMID:17308309 ADDLs stimulated excessive formation of reactive oxygen species (ROS) through a mechanism requiring N-methyl-d-aspartate receptor (NMDA-R) activation |
| GO:1905429 response to glycine | IDA PMID:28105280 GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive... | ACCEPT | Summary: Glycine acts as co-agonist on recombinant GluN1/GluN2A receptors in the modulator study. Reason: GluN1 carries the glycine site, and glycine binding there is required for channel opening, so the subunit directly mediates the response to glycine. Supporting Evidence: PMID:28105280 The N-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca2+ and Na+ file:human/GRIN1/GRIN1-uniprot.txt Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit |
| GO:2000463 positive regulation of excitatory postsynaptic potential | ISS GO_REF:0000024 | MODIFY | Summary: Author statements, a complex-level transfer and a transfer from rat GluN1 (PMID:12930820 and others). Reason: GluN1-containing receptors do not act on the excitatory postsynaptic potential from outside; their current is part of it. The donor work shows NMDA receptor subunits carrying synaptic currents. The potential itself is the accurate term and GRIN1 already carries it. Proposed replacements: excitatory postsynaptic potential Supporting Evidence: PMID:12930820 These currents were similar to synaptic currents recorded in neurons, and their decay kinetics was determined by the postsynaptic subunit combination PMID:8980238 Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning |
| GO:2000463 positive regulation of excitatory postsynaptic potential | ISS GO_REF:0000114 | MODIFY | Summary: Author statements, a complex-level transfer and a transfer from rat GluN1 (PMID:12930820 and others). Reason: GluN1-containing receptors do not act on the excitatory postsynaptic potential from outside; their current is part of it. The donor work shows NMDA receptor subunits carrying synaptic currents. The potential itself is the accurate term and GRIN1 already carries it. Proposed replacements: excitatory postsynaptic potential Supporting Evidence: PMID:12930820 These currents were similar to synaptic currents recorded in neurons, and their decay kinetics was determined by the postsynaptic subunit combination PMID:8980238 Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning |
| GO:2000463 positive regulation of excitatory postsynaptic potential | NAS PMID:15003177 Inducible and reversible NR1 knockout reveals crucial role o... | MODIFY | Summary: Author statements, a complex-level transfer and a transfer from rat GluN1 (PMID:12930820 and others). Reason: GluN1-containing receptors do not act on the excitatory postsynaptic potential from outside; their current is part of it. The donor work shows NMDA receptor subunits carrying synaptic currents. The potential itself is the accurate term and GRIN1 already carries it. Proposed replacements: excitatory postsynaptic potential Supporting Evidence: PMID:12930820 These currents were similar to synaptic currents recorded in neurons, and their decay kinetics was determined by the postsynaptic subunit combination PMID:8980238 Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning |
| GO:2000463 positive regulation of excitatory postsynaptic potential | NAS PMID:36959261 Distinct structure and gating mechanism in diverse NMDA rece... | MODIFY | Summary: Author statements, a complex-level transfer and a transfer from rat GluN1 (PMID:12930820 and others). Reason: GluN1-containing receptors do not act on the excitatory postsynaptic potential from outside; their current is part of it. The donor work shows NMDA receptor subunits carrying synaptic currents. The potential itself is the accurate term and GRIN1 already carries it. Proposed replacements: excitatory postsynaptic potential Supporting Evidence: PMID:12930820 These currents were similar to synaptic currents recorded in neurons, and their decay kinetics was determined by the postsynaptic subunit combination PMID:8980238 Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning |
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Download this section (compressed HTML)Q: Where and when do glycine-gated GluN1/GluN3 receptors operate in the human brain, and what fraction of GluN1 is assembled into them rather than into GluN2-containing receptors?
Q: Do presynaptic GluN1-containing receptors exist at human cortical and hippocampal synapses, and are they ionotropic there?
Q: Was the sodium channel activity annotation from PMID:21376300 based on direct recordings of sodium current, and was glutamate binding in PMID:7685113 measured by ligand binding or inferred from currents?
Q: Should the mouse Grin1 annotation to propylene metabolic process (PMID:21795692) be corrected at source, so that it stops propagating to orthologs?
Experiment: Record glycine-evoked currents in human iPSC-derived cortical neurons and in resected human cortical tissue in the presence of glycine-receptor and GluN2-selective blockers, with and without the GluN1 glycine-site antagonist CGP-78608 (which unmasks GluN1/GluN3A currents), and after GRIN3A knockdown.
Hypothesis: Glycine-gated GluN1/GluN3A receptors contribute a measurable tonic excitatory conductance in human neurons.
Type: patch-clamp electrophysiology with pharmacology and knockdown
Experiment: Measure binding of defined amyloid-beta oligomer preparations to purified human GluN1-GluN2B receptors reconstituted in nanodiscs by surface plasmon resonance, and compare oligomer binding to neurons with and without acute GluN1 depletion.
Hypothesis: Amyloid-beta oligomers do not bind GluN1 directly but associate with a neighbouring surface protein.
Type: in vitro binding assay with purified receptor
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