GRIN2B

Last updated
GRIN2B
Protein GRIN2B PDB 1S11.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GRIN2B , GluN2B, MRD6, NMDAR2B, NR2B, hNR3, EIEE27, glutamate ionotropic receptor NMDA type subunit 2B, NR3, DEE27
External IDs OMIM: 138252 MGI: 95821 HomoloGene: 646 GeneCards: GRIN2B
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000834

NM_008171
NM_001363750

RefSeq (protein)

NP_000825

NP_032197
NP_001350679

Location (UCSC) Chr 12: 13.44 – 13.98 Mb Chr 6: 135.69 – 136.15 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Glutamate [NMDA] receptor subunit epsilon-2, also known as N-methyl D-aspartate receptor subtype 2B (NMDAR2B or NR2B), is a protein that in humans is encoded by the GRIN2B gene. [5]

Contents

NMDA receptors

N-methyl-D-aspartate (NMDA) receptors are a class of ionotropic glutamate receptors. The NMDA receptor channel has been shown to be involved in long-term potentiation, an activity-dependent increase in the efficiency of synaptic transmission thought to underlie certain kinds of memory and learning. NMDA receptor channels are heterotetramers composed of two molecules of the key receptor subunit NMDAR1 (GRIN1) and two drawn from one or more of the four NMDAR2 subunits: NMDAR2A (GRIN2A), NMDAR2B (GRIN2B), NMDAR2C (GRIN2C), and NMDAR2D (GRIN2D). The NR2 subunit acts as the agonist binding site for glutamate, one of the predominant excitatory neurotransmitter receptors in the mammalian brain. [6]

Function

NR2B has been associated with age- and visual-experience-dependent plasticity in the neocortex of rats, where an increased NR2B/NR2A ratio correlates directly with the stronger excitatory LTP in young animals. This is thought to contribute to experience-dependent refinement of developing cortical circuits. [7]

Engineered to overexpress GRIN2B in their brains, mice and rats exhibit improved mental function. The "Doogie" mouse performed twice as well on one learning test. [8] [9]

Ligands

Interactions

GRIN2B has been shown to interact with:

See also

Related Research Articles

<i>N</i>-Methyl-<small>D</small>-aspartic acid Amino acid derivative

N-methyl-D-aspartic acid or N-methyl-D-aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike glutamate, NMDA only binds to and regulates the NMDA receptor and has no effect on other glutamate receptors. NMDA receptors are particularly important when they become overactive during, for example, withdrawal from alcohol as this causes symptoms such as agitation and, sometimes, epileptiform seizures.

<span class="mw-page-title-main">AMPA receptor</span> Transmembrane protein family

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is an ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synaptic transmission in the central nervous system (CNS). It has been traditionally classified as a non-NMDA-type receptor, along with the kainate receptor. Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. The GRIA2-encoded AMPA receptor ligand binding core was the first glutamate receptor ion channel domain to be crystallized.

<span class="mw-page-title-main">NMDA receptor</span> Glutamate receptor and ion channel protein found in nerve cells

The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.

<span class="mw-page-title-main">AP5</span> Chemical compound

AP5 is a chemical compound used as a biochemical tool to study various cellular processes. It is a selective NMDA receptor antagonist that competitively inhibits the ligand (glutamate) binding site of NMDA receptors. AP5 blocks NMDA receptors in micromolar concentrations.

<span class="mw-page-title-main">Ligand-gated ion channel</span> Type of ion channel transmembrane protein

Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

<span class="mw-page-title-main">Metabotropic glutamate receptor</span> Type of glutamate receptor

The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatory neurotransmitter.

<span class="mw-page-title-main">Glutamate receptor</span> Cell-surface proteins that bind glutamate and trigger changes which influence the behavior of cells

Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

<span class="mw-page-title-main">DLG4</span> Mammalian protein found in Homo sapiens

PSD-95 also known as SAP-90 is a protein that in humans is encoded by the DLG4 gene.

<span class="mw-page-title-main">DLG3</span> Protein-coding gene in the species Homo sapiens

Disks large homolog 3 (DLG3) also known as neuroendocrine-DLG or synapse-associated protein 102 (SAP-102) is a protein that in humans is encoded by the DLG3 gene. DLG3 is a member of the membrane-associated guanylate kinase (MAGUK) superfamily of proteins.

<span class="mw-page-title-main">GRIN2A</span> Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit epsilon-1 is a protein that in humans is encoded by the GRIN2A gene. With 1464 amino acids, the canonical GluN2A subunit isoform is large. GluN2A-short isoforms specific to primates can be produced by alternative splicing and contain 1281 amino acids.

<span class="mw-page-title-main">GRIN1</span> Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit zeta-1 is a protein that in humans is encoded by the GRIN1 gene.

<span class="mw-page-title-main">GRIN3A</span> Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit 3A is a protein that in humans is encoded by the GRIN3A gene.

<span class="mw-page-title-main">GRIN2D</span> Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit epsilon-4 is a protein that in humans is encoded by the GRIN2D gene.

<span class="mw-page-title-main">GRIN2C</span> Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit epsilon-3 is a protein that in humans is encoded by the GRIN2C gene.

<span class="mw-page-title-main">GRIN3B</span> Protein-coding gene in the species Homo sapiens

Glutamate [NMDA] receptor subunit 3B is a protein that in humans is encoded by the GRIN3B gene.

<span class="mw-page-title-main">DLGAP2</span> Protein-coding gene in the species Homo sapiens

Disks large-associated protein 2 is a protein that in humans is encoded by the DLGAP2 gene.

<span class="mw-page-title-main">Traxoprodil</span> Chemical compound

Traxoprodil is a drug developed by Pfizer which acts as an NMDA antagonist, selective for the NR2B subunit. It has neuroprotective, analgesic, and anti-Parkinsonian effects in animal studies. Traxoprodil has been researched in humans as a potential treatment to lessen the damage to the brain after stroke, but results from clinical trials showed only modest benefit. The drug was found to cause EKG abnormalities and its clinical development was stopped. More recent animal studies have suggested traxoprodil may exhibit rapid-acting antidepressant effects similar to those of ketamine, although there is some evidence for similar psychoactive side effects and abuse potential at higher doses, which might limit clinical acceptance of traxoprodil for this application.

Conantokins are a small family of helical peptides that are derived from the venom of predatory marine snails of the genus Conus. Conantokins act as potent and specific antagonists of the N-methyl-D-aspartate receptor (NMDAR). They are the only naturally-derived peptides to do so. The subtypes of conantokins exhibit a surprising variability of selectivity across the NMDAR subunits, and are therefore uniquely useful in developing subunit-specific pharmacological probes.

<span class="mw-page-title-main">Homoquinolinic acid</span> Chemical compound

Homoquinolinic acid (HQA) is a potent excitotoxin which is a conformationally-restricted analogue of N-methyl-D-aspartate (NMDA) and a partial agonist of the main/glutamate site of the NMDA receptor, with some selectivity for NR2B subunit-containing receptors. It is approximately equipotent to NMDA and about five times more potent than quinolinic acid as an agonist of the NMDA receptor. HQA has also been found to label a novel, yet uncharacterized binding site, which can be distinguished from the NMDA receptor with the use of 2-carboxy-3-carboxymethylquinoline (CCMQ), a selective ligand of the uncharacterized site.

GRIN disorders are a group of neurodevelopmental disorders that result from mutations in genes coding for subunits of an N-methyl-D-aspartate (NMDA) receptor, which leads to dysfunction of glutamate signaling. GRIN disorders are universally characterized by a varying degree of developmental delay and intellectual disability, as well as epileptic seizures. Other clinical features vary depending on the affected gene and may include muscular hypotonia, spasticity, and movement disorders. GRIN disorders are confirmed with genetic testing and managed symptomatically since there is currently no cure for the disorder.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000273079 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000030209 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B, Seeburg PH (May 1992). "Heteromeric NMDA receptors: molecular and functional distinction of subtypes". Science. 256 (5060): 1217–21. Bibcode:1992Sci...256.1217M. doi:10.1126/science.256.5060.1217. PMID   1350383. S2CID   989677.
  6. "Entrez Gene: GRIN2B glutamate receptor, ionotropic, N-methyl D-aspartate 2B".
  7. Yoshimura Y, Ohmura T, Komatsu Y (July 2003). "Two forms of synaptic plasticity with distinct dependence on age, experience, and NMDA receptor subtype in rat visual cortex". The Journal of Neuroscience. 23 (16): 6557–66. doi: 10.1523/JNEUROSCI.23-16-06557.2003 . PMC   6740618 . PMID   12878697.
  8. Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ (September 1999). "Genetic enhancement of learning and memory in mice". Nature. 401 (6748): 63–9. Bibcode:1999Natur.401...63T. doi:10.1038/43432. PMID   10485705. S2CID   481884.
  9. Wang D, Cui Z, Zeng Q, Kuang H, Wang LP, Tsien JZ, Cao X (October 2009). "Genetic enhancement of memory and long-term potentiation but not CA1 long-term depression in NR2B transgenic rats". PLOS ONE. 4 (10): e7486. Bibcode:2009PLoSO...4.7486W. doi: 10.1371/journal.pone.0007486 . PMC   2759522 . PMID   19838302.
  10. "The Effects of a Novel NMDA NR2B-Subtype Selective Antagonist, EVT 101, on Brain Function". Nct00526968. ClinicalTrials.gov. 2008-02-14. Retrieved 2010-08-19.
  11. "Phase II study with NR2B sub-type selective NMDA antagonist in treatment-resistant depression voluntarily terminated". evotec.com. 2011-05-18. Retrieved 2015-08-24.
  12. Wyszynski M, Lin J, Rao A, Nigh E, Beggs AH, Craig AM, Sheng M (January 1997). "Competitive binding of alpha-actinin and calmodulin to the NMDA receptor". Nature. 385 (6615): 439–42. Bibcode:1997Natur.385..439W. doi:10.1038/385439a0. PMID   9009191. S2CID   4266742.
  13. 1 2 3 Inanobe A, Fujita A, Ito M, Tomoike H, Inageda K, Kurachi Y (June 2002). "Inward rectifier K+ channel Kir2.3 is localized at the postsynaptic membrane of excitatory synapses". American Journal of Physiology. Cell Physiology. 282 (6): C1396–403. doi:10.1152/ajpcell.00615.2001. PMID   11997254.
  14. 1 2 3 Irie M, Hata Y, Takeuchi M, Ichtchenko K, Toyoda A, Hirao K, Takai Y, Rosahl TW, Südhof TC (September 1997). "Binding of neuroligins to PSD-95". Science. 277 (5331): 1511–5. doi:10.1126/science.277.5331.1511. PMID   9278515.
  15. 1 2 3 Sans N, Prybylowski K, Petralia RS, Chang K, Wang YX, Racca C, Vicini S, Wenthold RJ (June 2003). "NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex". Nature Cell Biology. 5 (6): 520–30. doi:10.1038/ncb990. PMID   12738960. S2CID   13444388.
  16. 1 2 Lim IA, Hall DD, Hell JW (June 2002). "Selectivity and promiscuity of the first and second PDZ domains of PSD-95 and synapse-associated protein 102". The Journal of Biological Chemistry. 277 (24): 21697–711. doi: 10.1074/jbc.M112339200 . PMID   11937501.
  17. Niethammer M, Valtschanoff JG, Kapoor TM, Allison DW, Weinberg RJ, Craig AM, Sheng M (April 1998). "CRIPT, a novel postsynaptic protein that binds to the third PDZ domain of PSD-95/SAP90". Neuron. 20 (4): 693–707. doi: 10.1016/s0896-6273(00)81009-0 . PMID   9581762. S2CID   16068361.
  18. Kornau HC, Schenker LT, Kennedy MB, Seeburg PH (September 1995). "Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95". Science. 269 (5231): 1737–40. Bibcode:1995Sci...269.1737K. doi:10.1126/science.7569905. PMID   7569905.
  19. Jo K, Derin R, Li M, Bredt DS (June 1999). "Characterization of MALS/Velis-1, -2, and -3: a family of mammalian LIN-7 homologs enriched at brain synapses in association with the postsynaptic density-95/NMDA receptor postsynaptic complex". The Journal of Neuroscience. 19 (11): 4189–99. doi: 10.1523/JNEUROSCI.19-11-04189.1999 . PMC   6782594 . PMID   10341223.
  20. Nakazawa T, Watabe AM, Tezuka T, Yoshida Y, Yokoyama K, Umemori H, Inoue A, Okabe S, Manabe T, Yamamoto T (July 2003). "p250GAP, a novel brain-enriched GTPase-activating protein for Rho family GTPases, is involved in the N-methyl-d-aspartate receptor signaling". Molecular Biology of the Cell. 14 (7): 2921–34. doi:10.1091/mbc.E02-09-0623. PMC   165687 . PMID   12857875.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.