GRIN2A explained

Glutamate [NMDA] receptor subunit epsilon-1 is a protein that in humans is encoded by the GRIN2A gene.^[1] 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.^{[2] [3]}

Function

N-methyl-D-aspartate (NMDA) receptors are a class of ionotropic glutamate receptors. NMDA 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 heteromers composed of the key receptor subunit NMDAR1 (GRIN1) and 1 or more of the 4 NMDAR2 subunits: NMDAR2A (GRIN2A), NMDAR2B (GRIN2B), NMDAR2C (GRIN2C), and NMDAR2D (GRIN2D).^[4]

Associations

Variants of the gene are associated with the protective effect of coffee on Parkinson's disease.^{[5] [6]}

Mutations in GRIN2A are associated to refractory epilepsy.^[7]

Whole exome/genome sequencing has led to the discovery of an association between mutations in GRIN2A and a wide variety of neurological diseases, including epilepsy, intellectual disability, autism spectrum disorders, developmental delay, and schizophrenia.^[8]

Interactions

GRIN2A has been shown to interact with:

• DLG1^[9]
  • DLG3 DLG4^{[10] [11] [12] [13]}
• FYN^{[14] [15] [16] [17]}
• Interleukin 16^[18]
• PTK2B^{[19] [20]}
• Src^{[15] [17]}

See also

• Glutamate receptor
• NMDA 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 . 683–688 . 1998 . 9745929 .
• King JE, Eugenin EA, Buckner CM, Berman JW . HIV tat and neurotoxicity . Microbes and Infection . 8 . 5 . 1347–1357 . April 2006 . 16697675 . 10.1016/j.micinf.2005.11.014 . free .
• Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B, Seeburg PH . 6 . Heteromeric NMDA receptors: molecular and functional distinction of subtypes . Science . 256 . 5060 . 1217–1221 . May 1992 . 1350383 . 10.1126/science.256.5060.1217 . 989677 . 1992Sci...256.1217M .
• Kornau HC, Schenker LT, Kennedy MB, Seeburg PH . Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95 . Science . 269 . 5231 . 1737–1740 . 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 . 373–380 . March 1995 . 7695237 . 10.1002/ana.410370314 . 24405132 .
• Sakimura K, Kutsuwada T, Ito I, Manabe T, Takayama C, Kushiya E, Yagi T, Aizawa S, Inoue Y, Sugiyama H . 6 . Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit . Nature . 373 . 6510 . 151–155 . January 1995 . 7816096 . 10.1038/373151a0 . 4356780 .
• Foldes RL, Adams SL, Fantaske RP, Kamboj RK . Human N-methyl-D-aspartate receptor modulatory subunit hNR2A: cloning and sequencing of the cDNA and primary structure of the protein . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1223 . 1 . 155–159 . August 1994 . 8061049 . 10.1016/0167-4889(94)90086-8 .
• 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 . 144–147 . March 1994 . 8139656 . 10.1038/368144a0 . 4332025 . 1994Natur.368..144S .
• Roche KW, Raymond LA, Blackstone C, Huganir RL . Transmembrane topology of the glutamate receptor subunit GluR6 . The Journal of Biological Chemistry . 269 . 16 . 11679–11682 . April 1994 . 8163463 . 10.1016/S0021-9258(17)32623-6 . free .
• Takano H, Onodera O, Tanaka H, Mori H, Sakimura K, Hori T, Kobayashi H, Mishina M, Tsuji S . 6 . Chromosomal localization of the epsilon 1, epsilon 3 and zeta 1 subunit genes of the human NMDA receptor channel . Biochemical and Biophysical Research Communications . 197 . 2 . 922–926 . December 1993 . 8267632 . 10.1006/bbrc.1993.2567 .
• 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 . 2285–2293 . 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 . 315–321 . 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 . 2157–2163 . April 1996 . 8601796 . 6578538 . 10.1523/JNEUROSCI.16-07-02157.1996 . 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 . 463–468 . 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 . 6 . Cloning and functional characterization of human heteromeric N-methyl-D-aspartate receptors . The Journal of Pharmacology and Experimental Therapeutics . 278 . 2 . 808–816 . August 1996 . 8768735 .
• 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 . 1045–1049 . 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 . 168–176 . 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 . 303–307 . 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 . 2502–2507 . December 1995 . 8845955 . 10.1111/j.1460-9568.1995.tb01048.x . 7370984 .
• Raber J, Toggas SM, Lee S, Bloom FE, Epstein CJ, Mucke L . Central nervous system expression of HIV-1 Gp120 activates the hypothalamic-pituitary-adrenal axis: evidence for involvement of NMDA receptors and nitric oxide synthase . Virology . 226 . 2 . 362–373 . December 1996 . 8955056 . 10.1006/viro.1996.0664 . free .

Notes and References

1. Kalsi G, Whiting P, Bourdelles BL, Callen D, Barnard EA, Gurling H . Localization of the human NMDAR2D receptor subunit gene (GRIN2D) to 19q13.1-qter, the NMDAR2A subunit gene to 16p13.2 (GRIN2A), and the NMDAR2C subunit gene (GRIN2C) to 17q24-q25 using somatic cell hybrid and radiation hybrid mapping panels . Genomics . 47 . 3 . 423–425 . February 1998 . 9480759 . 10.1006/geno.1997.5132 .
2. Warming H, Pegasiou CM, Pitera AP, Kariis H, Houghton SD, Kurbatskaya K, Ahmed A, Grundy P, Vajramani G, Bulters D, Altafaj X, Deinhardt K, Vargas-Caballero M . 6 . A primate-specific short GluN2A-NMDA receptor isoform is expressed in the human brain . Molecular Brain . 12 . 1 . 64 . July 2019 . 31272478 . 6610962 . 10.1186/s13041-019-0485-9 . free .
3. Herbrechter R, Hube N, Buchholz R, Reiner A . Splicing and editing of ionotropic glutamate receptors: a comprehensive analysis based on human RNA-Seq data . Cellular and Molecular Life Sciences . 78 . 14 . 5605–5630 . July 2021 . 34100982 . 8257547 . 10.1007/s00018-021-03865-z .
4. Web site: Entrez Gene: GRIN2A glutamate receptor, ionotropic, N-methyl D-aspartate 2A.
5. Hamza TH, Chen H, Hill-Burns EM, Rhodes SL, Montimurro J, Kay DM, Tenesa A, Kusel VI, Sheehan P, Eaaswarkhanth M, Yearout D, Samii A, Roberts JW, Agarwal P, Bordelon Y, Park Y, Wang L, Gao J, Vance JM, Kendler KS, Bacanu SA, Scott WK, Ritz B, Nutt J, Factor SA, Zabetian CP, Payami H . 6 . Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee . PLOS Genetics . 7 . 8 . e1002237 . August 2011 . 21876681 . 3158052 . 10.1371/journal.pgen.1002237 . free .
6. Yamada-Fowler N, Fredrikson M, Söderkvist P . Caffeine interaction with glutamate receptor gene GRIN2A: Parkinson's disease in Swedish population . PLOS ONE . 9 . 6 . e99294 . June 2014 . 24915238 . 4051678 . 10.1371/journal.pone.0099294 . free . 2014PLoSO...999294Y .
7. Venkateswaran S, Myers KA, Smith AC, Beaulieu CL, Schwartzentruber JA, Majewski J, Bulman D, Boycott KM, Dyment DA . 6 . Whole-exome sequencing in an individual with severe global developmental delay and intractable epilepsy identifies a novel, de novo GRIN2A mutation . Epilepsia . 55 . 7 . e75–e79 . July 2014 . 24903190 . 10.1111/epi.12663 . 205116246 . free .
8. Yuan H, Low CM, Moody OA, Jenkins A, Traynelis SF . Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases . Molecular Pharmacology . 88 . 1 . 203–217 . July 2015 . 25904555 . 4468639 . 10.1124/mol.115.097998 .
9. Gardoni F, Mauceri D, Fiorentini C, Bellone C, Missale C, Cattabeni F, Di Luca M . CaMKII-dependent phosphorylation regulates SAP97/NR2A interaction . The Journal of Biological Chemistry . 278 . 45 . 44745–44752 . November 2003 . 12933808 . 10.1074/jbc.M303576200 . free .
10. Irie M, Hata Y, Takeuchi M, Ichtchenko K, Toyoda A, Hirao K, Takai Y, Rosahl TW, Südhof TC . 6 . Binding of neuroligins to PSD-95 . Science . 277 . 5331 . 1511–1515 . September 1997 . 9278515 . 10.1126/science.277.5331.1511 .
11. 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 . 21697–21711 . June 2002 . 11937501 . 10.1074/jbc.M112339200 . free .
12. Satoh K, Yanai H, Senda T, Kohu K, Nakamura T, Okumura N, Matsumine A, Kobayashi S, Toyoshima K, Akiyama T . 6 . DAP-1, a novel protein that interacts with the guanylate kinase-like domains of hDLG and PSD-95 . Genes to Cells . 2 . 6 . 415–424 . June 1997 . 9286858 . 10.1046/j.1365-2443.1997.1310329.x . 8934092 . free .
13. Sans N, Petralia RS, Wang YX, Blahos J, Hell JW, Wenthold RJ . A developmental change in NMDA receptor-associated proteins at hippocampal synapses . The Journal of Neuroscience . 20 . 3 . 1260–1271 . February 2000 . 10648730 . 6774158 . 10.1523/JNEUROSCI.20-03-01260.2000 . free .
14. Hou XY, Zhang GY, Yan JZ, Chen M, Liu Y . Activation of NMDA receptors and L-type voltage-gated calcium channels mediates enhanced formation of Fyn-PSD95-NR2A complex after transient brain ischemia . Brain Research . 955 . 1–2 . 123–132 . November 2002 . 12419528 . 10.1016/s0006-8993(02)03376-0 . 85751 .
15. Ma J, Zhang GY . Lithium reduced N-methyl-D-aspartate receptor subunit 2A tyrosine phosphorylation and its interactions with Src and Fyn mediated by PSD-95 in rat hippocampus following cerebral ischemia . Neuroscience Letters . 348 . 3 . 185–189 . September 2003 . 12932824 . 10.1016/s0304-3940(03)00784-5 . 40684016 .
16. Tezuka T, Umemori H, Akiyama T, Nakanishi S, Yamamoto T . PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A . Proceedings of the National Academy of Sciences of the United States of America . 96 . 2 . 435–440 . January 1999 . 9892651 . 15154 . 10.1073/pnas.96.2.435 . free . 1999PNAS...96..435T .
17. Takagi N, Cheung HH, Bissoon N, Teves L, Wallace MC, Gurd JW . The effect of transient global ischemia on the interaction of Src and Fyn with the N-methyl-D-aspartate receptor and postsynaptic densities: possible involvement of Src homology 2 domains . Journal of Cerebral Blood Flow and Metabolism . 19 . 8 . 880–888 . August 1999 . 10458595 . 10.1097/00004647-199908000-00007 . free .
18. Kurschner C, Yuzaki M . Neuronal interleukin-16 (NIL-16): a dual function PDZ domain protein . The Journal of Neuroscience . 19 . 18 . 7770–7780 . September 1999 . 10479680 . 6782450 . 10.1523/JNEUROSCI.19-18-07770.1999 . free .
19. Seabold GK, Burette A, Lim IA, Weinberg RJ, Hell JW . Interaction of the tyrosine kinase Pyk2 with the N-methyl-D-aspartate receptor complex via the Src homology 3 domains of PSD-95 and SAP102 . The Journal of Biological Chemistry . 278 . 17 . 15040–15048 . April 2003 . 12576483 . 10.1074/jbc.M212825200 . free .
20. Liu Y, Zhang G, Gao C, Hou X . NMDA receptor activation results in tyrosine phosphorylation of NMDA receptor subunit 2A(NR2A) and interaction of Pyk2 and Src with NR2A after transient cerebral ischemia and reperfusion . Brain Research . 909 . 1–2 . 51–58 . August 2001 . 11478920 . 10.1016/s0006-8993(01)02619-1 . 21062909 .