GRIN2B explained

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.^[1]

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.^[2]

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.^[3]

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.^{[4] [5]}

Ligands

• Besonprodil
• CERC-301, a selective NR2B receptor antagonist
• Eliprodil
• Ethanol - apparent induction of dephosphorylation of the NR2B Tyr1472 residue by STEP, leading to reduced receptor function
• Ifenprodil
  • Rislenemdaz EVT-101, a selective NR2B receptor antagonist. This compound was tested as a potentially fast-acting antidepressant.^[6] In 2011 it was voluntarily withdrawn from a Phase II clinical study in treatment-resistant depression due to an unsatisfactory toxicity profile.^[7]
• Felbamate, an anticonvulsant that is also a positive allosteric modulator for the GABA_A receptor
• Ro-25-6981 (also known as MI-4), a selective NR2B receptor antagonist
• Traxoprodil, a selective NR2B receptor antagonist
• Toluene - noncompetitive antagonist

Interactions

GRIN2B has been shown to interact with:

• Actinin, alpha 2,^[8]
• DLG2,
• DLG3,
• DLG4,^{[9] [10] [11] [12] [13] [14]}
• EXOC4,^[11]
• LIN7B,^[15] and
• RICS.^[16]

See also

• NMDA receptor
• Glutamate receptor

Further reading

• Schröder HC, Perovic S, Kavsan V, Ushijima H, Müller WE . Mechanisms of prionSc- and HIV-1 gp120 induced neuronal cell death . Neurotoxicology . 19 . 4–5 . 683–8 . 1998 . 9745929 .
• Nagy J . The NR2B subtype of NMDA receptor: a potential target for the treatment of alcohol dependence . Current Drug Targets. CNS and Neurological Disorders . 3 . 3 . 169–79 . June 2004 . 15180478 . 10.2174/1568007043337409 .
• King JE, Eugenin EA, Buckner CM, Berman JW . HIV tat and neurotoxicity . Microbes and Infection . 8 . 5 . 1347–57 . April 2006 . 16697675 . 10.1016/j.micinf.2005.11.014 . free .
• Kornau HC, Schenker LT, Kennedy MB, Seeburg PH . Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95 . Science . 269 . 5231 . 1737–40 . September 1995 . 7569905 . 10.1126/science.7569905 . 1995Sci...269.1737K .
• Magnuson DS, Knudsen BE, Geiger JD, Brownstone RM, Nath A . Human immunodeficiency virus type 1 tat activates non-N-methyl-D-aspartate excitatory amino acid receptors and causes neurotoxicity . Annals of Neurology . 37 . 3 . 373–80 . March 1995 . 7695237 . 10.1002/ana.410370314 . 24405132 .
• Mandich P, Schito AM, Bellone E, Antonacci R, Finelli P, Rocchi M, Ajmar F . Mapping of the human NMDAR2B receptor subunit gene (GRIN2B) to chromosome 12p12 . Genomics . 22 . 1 . 216–8 . July 1994 . 7959773 . 10.1006/geno.1994.1366 .
• Adams SL, Foldes RL, Kamboj RK . Human N-methyl-D-aspartate receptor modulatory subunit hNR3: cloning and sequencing of the cDNA and primary structure of the protein . Biochimica et Biophysica Acta . 1260 . 1 . 105–8 . January 1995 . 7999784 . 10.1016/0167-4781(94)00189-a .
• Sheng M, Cummings J, Roldan LA, Jan YN, Jan LY . Changing subunit composition of heteromeric NMDA receptors during development of rat cortex . Nature . 368 . 6467 . 144–7 . March 1994 . 8139656 . 10.1038/368144a0 . 1994Natur.368..144S . 4332025 .
• Roche KW, Raymond LA, Blackstone C, Huganir RL . Transmembrane topology of the glutamate receptor subunit GluR6 . The Journal of Biological Chemistry . 269 . 16 . 11679–82 . April 1994 . 10.1016/S0021-9258(17)32623-6 . 8163463 . free .
• Lannuzel A, Lledo PM, Lamghitnia HO, Vincent JD, Tardieu M . HIV-1 envelope proteins gp120 and gp160 potentiate NMDA-induced [Ca2+]i increase, alter [Ca2+]i homeostasis and induce neurotoxicity in human embryonic neurons . The European Journal of Neuroscience . 7 . 11 . 2285–93 . November 1995 . 8563977 . 10.1111/j.1460-9568.1995.tb00649.x . 27201873 .
• Corasaniti MT, Melino G, Navarra M, Garaci E, Finazzi-Agrò A, Nisticò G . Death of cultured human neuroblastoma cells induced by HIV-1 gp120 is prevented by NMDA receptor antagonists and inhibitors of nitric oxide and cyclooxygenase . Neurodegeneration . 4 . 3 . 315–21 . September 1995 . 8581564 . 10.1016/1055-8330(95)90021-7 .
• Niethammer M, Kim E, Sheng M . Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases . The Journal of Neuroscience . 16 . 7 . 2157–63 . April 1996 . 8601796 . 10.1523/JNEUROSCI.16-07-02157.1996. 6578538 . free .
• Pittaluga A, Pattarini R, Severi P, Raiteri M . Human brain N-methyl-D-aspartate receptors regulating noradrenaline release are positively modulated by HIV-1 coat protein gp120 . AIDS . 10 . 5 . 463–8 . May 1996 . 8724036 . 10.1097/00002030-199605000-00003 . 1669986 .
• Hess SD, Daggett LP, Crona J, Deal C, Lu CC, Urrutia A, Chavez-Noriega L, Ellis SB, Johnson EC, Veliçelebi G . Cloning and functional characterization of human heteromeric N-methyl-D-aspartate receptors . The Journal of Pharmacology and Experimental Therapeutics . 278 . 2 . 808–16 . August 1996 . 8768735 .
• Müller BM, Kistner U, Kindler S, Chung WJ, Kuhlendahl S, Fenster SD, Lau LF, Veh RW, Huganir RL, Gundelfinger ED, Garner CC . SAP102, a novel postsynaptic protein that interacts with NMDA receptor complexes in vivo . Neuron . 17 . 2 . 255–65 . August 1996 . 8780649 . 10.1016/S0896-6273(00)80157-9 . 18715321 . free .
• Wu P, Price P, Du B, Hatch WC, Terwilliger EF . Direct cytotoxicity of HIV-1 envelope protein gp120 on human NT neurons . NeuroReport . 7 . 5 . 1045–9 . April 1996 . 8804048 . 10.1097/00001756-199604100-00018 . 21018147 .
• Bennett BA, Rusyniak DE, Hollingsworth CK . HIV-1 gp120-induced neurotoxicity to midbrain dopamine cultures . Brain Research . 705 . 1–2 . 168–76 . December 1995 . 8821747 . 10.1016/0006-8993(95)01166-8 . 32822686 .
• Toggas SM, Masliah E, Mucke L . Prevention of HIV-1 gp120-induced neuronal damage in the central nervous system of transgenic mice by the NMDA receptor antagonist memantine . Brain Research . 706 . 2 . 303–7 . January 1996 . 8822372 . 10.1016/0006-8993(95)01197-8 . 44260060 .
• Dreyer EB, Lipton SA . The coat protein gp120 of HIV-1 inhibits astrocyte uptake of excitatory amino acids via macrophage arachidonic acid . The European Journal of Neuroscience . 7 . 12 . 2502–7 . December 1995 . 8845955 . 10.1111/j.1460-9568.1995.tb01048.x . 7370984 .

Notes and References

1. Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B, Seeburg PH . Heteromeric NMDA receptors: molecular and functional distinction of subtypes . Science . 256 . 5060 . 1217–21 . May 1992 . 1350383 . 10.1126/science.256.5060.1217 . 1992Sci...256.1217M . 989677 .
2. Web site: Entrez Gene: GRIN2B glutamate receptor, ionotropic, N-methyl D-aspartate 2B.
3. Yoshimura Y, Ohmura T, Komatsu Y . 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 . July 2003 . 12878697 . 10.1523/JNEUROSCI.23-16-06557.2003 . 6740618 . free .
4. Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ . Genetic enhancement of learning and memory in mice . Nature . 401 . 6748 . 63–9 . September 1999 . 10485705 . 10.1038/43432 . 1999Natur.401...63T . 481884 .
5. Wang D, Cui Z, Zeng Q, Kuang H, Wang LP, Tsien JZ, Cao X . Genetic enhancement of memory and long-term potentiation but not CA1 long-term depression in NR2B transgenic rats . PLOS ONE . 4 . 10 . e7486 . October 2009 . 19838302 . 10.1371/journal.pone.0007486 . 2759522. 2009PLoSO...4.7486W . free .
6. The Effects of a Novel NMDA NR2B-Subtype Selective Antagonist, EVT 101, on Brain Function . 2008-02-14 . Nct00526968 . ClinicalTrials.gov . 2010-08-19 .
7. Web site: Phase II study with NR2B sub-type selective NMDA antagonist in treatment-resistant depression voluntarily terminated . 2011-05-18 . evotec.com . 2015-08-24 .
8. Wyszynski M, Lin J, Rao A, Nigh E, Beggs AH, Craig AM, Sheng M . Competitive binding of alpha-actinin and calmodulin to the NMDA receptor . Nature . 385 . 6615 . 439–42 . January 1997 . 9009191 . 10.1038/385439a0 . 1997Natur.385..439W . 4266742 .
9. Inanobe A, Fujita A, Ito M, Tomoike H, Inageda K, Kurachi Y . 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 . June 2002 . 11997254 . 10.1152/ajpcell.00615.2001 .
10. Irie M, Hata Y, Takeuchi M, Ichtchenko K, Toyoda A, Hirao K, Takai Y, Rosahl TW, Südhof TC . Binding of neuroligins to PSD-95 . Science . 277 . 5331 . 1511–5 . September 1997 . 9278515 . 10.1126/science.277.5331.1511 .
11. Sans N, Prybylowski K, Petralia RS, Chang K, Wang YX, Racca C, Vicini S, Wenthold RJ . NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex . Nature Cell Biology . 5 . 6 . 520–30 . June 2003 . 12738960 . 10.1038/ncb990 . 13444388 .
12. Lim IA, Hall DD, Hell JW . 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 . June 2002 . 11937501 . 10.1074/jbc.M112339200 . free .
13. Niethammer M, Valtschanoff JG, Kapoor TM, Allison DW, Weinberg RJ, Craig AM, Sheng M . CRIPT, a novel postsynaptic protein that binds to the third PDZ domain of PSD-95/SAP90 . Neuron . 20 . 4 . 693–707 . April 1998 . 9581762 . 10.1016/s0896-6273(00)81009-0 . 16068361 . free .
14. Kornau HC, Schenker LT, Kennedy MB, Seeburg PH . Mary B. Kennedy. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95 . Science . 269 . 5231 . 1737–40 . September 1995 . 7569905 . 10.1126/science.7569905 . 1995Sci...269.1737K.
15. Jo K, Derin R, Li M, Bredt DS . 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 . June 1999 . 10341223 . 10.1523/JNEUROSCI.19-11-04189.1999. 6782594 . free .
16. Nakazawa T, Watabe AM, Tezuka T, Yoshida Y, Yokoyama K, Umemori H, Inoue A, Okabe S, Manabe T, Yamamoto T . 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 . July 2003 . 12857875 . 165687 . 10.1091/mbc.E02-09-0623 .