GRID2

GluD2-containing receptors are selectively/predominantly expressed in Purkinje cells in the cerebellum{{cite journal | vauthors = Araki K, Meguro H, Kushiya E, Takayama C, Inoue Y, Mishina M | title = Selective expression of the glutamate receptor channel delta 2 subunit in cerebellar Purkinje cells | journal = Biochemical and Biophysical Research Communications | volume = 197 | issue = 3 | pages = 1267–76 | date = Dec 1993 | pmid = 7506541 | doi = 10.1006/bbrc.1993.2614 }} where they play a key role in synaptogenesis, synaptic plasticity, and motor coordination.{{cite journal | vauthors = Yuzaki M | title = Cerebellar LTD vs. motor learning-lessons learned from studying GluD2 | journal = Neural Networks | volume = 47 | pages = 36–41 | date = Nov 2013 | pmid = 22840919 | doi = 10.1016/j.neunet.2012.07.001 }}

GluD2 induces synaptogenesis through interaction of its N-terminal domain with Cbln1, which in turn interacts with presynaptic neurexins, forming a bridge across cerebellar synapses.{{cite journal | vauthors = Matsuda K, Yuzaki M | title = Cbln1 and the δ2 glutamate receptor--an orphan ligand and an orphan receptor find their partners | journal = Cerebellum | volume = 11 | issue = 1 | pages = 78–84 | date = Mar 2012 | pmid = 20535596 | doi = 10.1007/s12311-010-0186-5 | s2cid = 16612844 }}

The main functions of GluD2 in synaptic plasticity are carried out by its intracellular C-terminus.{{cite journal | vauthors = Kakegawa W, Miyazaki T, Emi K, Matsuda K, Kohda K, Motohashi J, Mishina M, Kawahara S, Watanabe M, Yuzaki M | title = Differential regulation of synaptic plasticity and cerebellar motor learning by the C-terminal PDZ-binding motif of GluRdelta2 | journal = J. Neurosci. | volume = 28 | issue = 6 | pages = 1460–1468 | date = February 2008 | pmid = 18256267 | doi = 10.1523/JNEUROSCI.2553-07.2008 | pmc = 6671576 | url = https://zenodo.org/record/894323 }} This is regulated by D-serine,{{cite journal | vauthors = Kakegawa W, Miyoshi Y, Hamase K, Matsuda S, Matsuda K, Kohda K, Emi K, Motohashi J, Konno R, Zaitsu K, Yuzaki M | title = D-serine regulates cerebellar LTD and motor coordination through the δ2 glutamate receptor | journal = Nat. Neurosci. | volume = 14 | issue = 5 | pages = 603–611 | date = May 2011 | pmid = 21460832 | doi = 10.1038/nn.2791 | s2cid = 17507539 }} which binds to the ligand-binding domain and results in changes in the structure of GluD2 without opening the channel in the absence of pre-synaptic connections. Glycine and D-serine can open the channel in GluD2 when bound to cerebellin-1 and neurexin-1β.{{Cite journal|last1=Carrillo|first1=Elisa|last2=Gonzalez|first2=Cuauhtemoc U.|last3=Berka|first3=Vladimir|last4=Jayaraman|first4=Vasanthi|date=2021-12-24|title=Delta glutamate receptors are functional glycine- and ᴅ-serine–gated cation channels in situ|journal=Science Advances|language=en|volume=7|issue=52|pages=eabk2200|doi=10.1126/sciadv.abk2200|issn=2375-2548|pmc=8694607|pmid=34936451|bibcode=2021SciA....7.2200C }} These changes may signal up to the N-terminal domain or down to the C-terminal domain to alter protein-protein interactions.

A heterozygous deletion in GRID2 in humans causes a complicated spastic paraplegia with ataxia, frontotemporal dementia, and lower motor neuron involvement{{cite journal | vauthors = Maier A, Klopocki E, Horn D, Tzschach A, Holm T, Meyer R, Meyer T | title = De novo partial deletion in GRID2 presenting with complicated spastic paraplegia | journal = Muscle & Nerve | volume = 49 | issue = 2 | pages = 289–92 | date = Feb 2014 | pmid = 24122788 | doi = 10.1002/mus.24096 | s2cid = 26359325 }} whereas a homozygous biallelic deletion leads to a syndrome of cerebellar ataxia with marked developmental delay, pyramidal tract involvement{{cite journal | vauthors = Utine GE, Haliloğlu G, Salanci B, Çetinkaya A, Kiper PÖ, Alanay Y, Aktas D, Boduroğlu K, Alikaşifoğlu M | title = A homozygous deletion in GRID2 causes a human phenotype with cerebellar ataxia and atrophy | journal = Journal of Child Neurology | volume = 28 | issue = 7 | pages = 926–32 | date = Jul 2013 | pmid = 23611888 | doi = 10.1177/0883073813484967 | s2cid = 206550612 }} and tonic upgaze,{{cite journal | vauthors = Hills LB, Masri A, Konno K, Kakegawa W, Lam AT, Lim-Melia E, Chandy N, Hill RS, Partlow JN, Al-Saffar M, Nasir R, Stoler JM, Barkovich AJ, Watanabe M, Yuzaki M, Mochida GH | title = Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans | journal = Neurology | volume = 81 | issue = 16 | pages = 1378–86 | date = Oct 2013 | pmid = 24078737 | doi = 10.1212/WNL.0b013e3182a841a3 | pmc=3806907}} that can be classified as an ataxia with oculomotor apraxia (AOA) and has been named spinocerebellar ataxia, autosomal recessive type 18 (SCAR18).

A gain of channel function, resulting from a point mutation in mouse GRID2, is associated with the phenotype named 'lurcher', which in the heterozygous state leads to ataxia and motor coordination deficits resulting from selective, cell-autonomous apoptosis of cerebellar Purkinje cells during postnatal development.{{cite journal | vauthors = Lalonde R, Botez MI, Joyal CC, Caumartin M | title = Motor abnormalities in lurcher mutant mice | journal = Physiology & Behavior | volume = 51 | issue = 3 | pages = 523–5 | date = Mar 1992 | pmid = 1523229 | doi = 10.1016/0031-9384(92)90174-Z | s2cid = 33424240 }}{{cite journal | vauthors = Zuo J, De Jager PL, Takahashi KA, Jiang W, Linden DJ, Heintz N | title = Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene | journal = Nature | volume = 388 | issue = 6644 | pages = 769–73 | date = Aug 1997 | pmid = 9285588 | doi = 10.1038/42009 | bibcode = 1997Natur.388..769Z | s2cid = 4431774 | doi-access = free }} Mice homozygous for this mutation die shortly after birth from massive loss of mid- and hindbrain neurons during late embryogenesis.

9-Aminoacridine, 9-tetrahydroaminoacridine, N1-dansyl-spermine, N1-dansyl-spermidine, and pentamidine have been shown to act as antagonists of δ₂-containing receptors.{{cite journal | vauthors = Williams K, Dattilo M, Sabado TN, Kashiwagi K, Igarashi K | title = Pharmacology of delta2 glutamate receptors: effects of pentamidine and protons | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 305 | issue = 2 | pages = 740–8 | date = May 2003 | pmid = 12606689 | doi = 10.1124/jpet.102.045799 | s2cid = 83540259 }}

GRID2 has been shown to interact with GOPC,{{cite journal | vauthors = Yue Z, Horton A, Bravin M, DeJager PL, Selimi F, Heintz N | title = A novel protein complex linking the delta 2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice | journal = Neuron | volume = 35 | issue = 5 | pages = 921–33 | date = Aug 2002 | pmid = 12372286 | doi = 10.1016/S0896-6273(02)00861-9 | s2cid = 10534933 | doi-access = free }} GRIK2,{{cite journal | vauthors = Kohda K, Kamiya Y, Matsuda S, Kato K, Umemori H, Yuzaki M | title = Heteromer formation of delta2 glutamate receptors with AMPA or kainate receptors | journal = Brain Research. Molecular Brain Research | volume = 110 | issue = 1 | pages = 27–37 | date = Jan 2003 | pmid = 12573530 | doi = 10.1016/S0169-328X(02)00561-2 }} PTPN4{{cite journal | vauthors = Hironaka K, Umemori H, Tezuka T, Mishina M, Yamamoto T | title = The protein-tyrosine phosphatase PTPMEG interacts with glutamate receptor delta 2 and epsilon subunits | journal = The Journal of Biological Chemistry | volume = 275 | issue = 21 | pages = 16167–73 | date = May 2000 | pmid = 10748123 | doi = 10.1074/jbc.M909302199 | doi-access = free }} and GRIA1. A possible correlation between GRID2 and the pre-B lymphocyte protein 3 (VPREB3) has been suggested, due to the apparent importance of B-lymphocytes in the origins of cerebellar Purkinje neurons in humans.{{cite journal | vauthors = Hess DC, Hill WD, Carroll JE, Borlongan CV | title = Do bone marrow cells generate neurons? | journal = Archives of Neurology | volume = 61 | issue = 4 | pages = 483–5 | date = Apr 2004 | pmid = 15096394 | doi = 10.1001/archneur.61.4.483 | url = https://www.researchgate.net/publication/8608203 | doi-access = free }}{{cite journal | vauthors = Weimann JM, Johansson CB, Trejo A, Blau HM | title = Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant | journal = Nature Cell Biology | volume = 5 | issue = 11 | pages = 959–66 | date = Nov 2003 | pmid = 14562057 | doi = 10.1038/ncb1053 | s2cid = 33685652 | url = https://www.researchgate.net/publication/9048544 }}{{cite journal | vauthors = Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A | title = Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes | journal = Nature | volume = 425 | issue = 6961 | pages = 968–73 | date = Oct 2003 | pmid = 14555960 | doi = 10.1038/nature02069 | bibcode = 2003Natur.425..968A | url = https://www.researchgate.net/publication/9053693 | hdl = 2027.42/62789 | s2cid = 4394453 | hdl-access = free }}{{cite journal | vauthors = Felizola SJ, Katsu K, Ise K, Nakamura Y, Arai Y, Satoh F, Sasano H | title = Pre-B Lymphocyte Protein 3 (VPREB3) Expression in the Adrenal Cortex: Precedent for non-Immunological Roles in Normal and Neoplastic Human Tissues | journal = Endocrine Pathology | volume = 26 | issue = 2 | pages = 119–28 | date = May 2015 | pmid = 25861052 | doi = 10.1007/s12022-015-9366-7 | s2cid = 27271366 | url = https://www.researchgate.net/publication/274075697 }}{{cite journal | vauthors = Kemp K, Wilkins A, Scolding N | title = Cell fusion in the brain: two cells forward, one cell back | journal = Acta Neuropathologica | volume = 128 | issue = 5 | pages = 629–38 | date = Nov 2014 | pmid = 24899142 | doi = 10.1007/s00401-014-1303-1 | pmc=4201757}} Morphological studies conducted in GRID2-knockout mice suggest that GRID2 may be present in lymphocytes as well as in the adrenal cortex, however further studies must be conducted to confirm these claims.{{cite journal|vauthors=Berenova M, Mandakova P, Sima P, Slipka J, Vozeh F, Kocova J, Cervinkova M, Sykora J | title= Morphology of Adrenal Gland and Lymph Organs is Impaired in Neurodeficient Lurcher Mutant Mice.|journal= Acta Vet. Brno |volume= 71 |pages= 23–28 |year= 2002 |doi= 10.2754/avb200271010023 |doi-access= free }}

• GRID1

{{Reflist|2}}

{{Refbegin|2}}

• {{cite journal | vauthors = Araki K, Meguro H, Kushiya E, Takayama C, Inoue Y, Mishina M | title = Selective expression of the glutamate receptor channel delta 2 subunit in cerebellar Purkinje cells | journal = Biochemical and Biophysical Research Communications | volume = 197 | issue = 3 | pages = 1267–76 | date = Dec 1993 | pmid = 7506541 | doi = 10.1006/bbrc.1993.2614 }}
• {{cite journal | vauthors = Hu W, Zuo J, De Jager PL, Heintz N | title = The human glutamate receptor delta 2 gene (GRID2) maps to chromosome 4q22 | journal = Genomics | volume = 47 | issue = 1 | pages = 143–5 | date = Jan 1998 | pmid = 9465309 | doi = 10.1006/geno.1997.5108 }}
• {{cite journal | title = Toward a complete human genome sequence | journal = Genome Research | volume = 8 | issue = 11 | pages = 1097–108 | date = Nov 1998 | pmid = 9847074 | doi = 10.1101/gr.8.11.1097 | last1 = Sanger Centre | first1 = The | last2 = Washington University Genome Sequencing Cente | first2 = The | doi-access = free }}
• {{cite journal | vauthors = Roche KW, Ly CD, Petralia RS, Wang YX, McGee AW, Bredt DS, Wenthold RJ | title = Postsynaptic density-93 interacts with the delta2 glutamate receptor subunit at parallel fiber synapses | journal = The Journal of Neuroscience | volume = 19 | issue = 10 | pages = 3926–34 | date = May 1999 | pmid = 10234023 | doi = 10.1523/JNEUROSCI.19-10-03926.1999| pmc = 6782719 | doi-access = free }}
• {{cite journal | vauthors = Hironaka K, Umemori H, Tezuka T, Mishina M, Yamamoto T | title = The protein-tyrosine phosphatase PTPMEG interacts with glutamate receptor delta 2 and epsilon subunits | journal = The Journal of Biological Chemistry | volume = 275 | issue = 21 | pages = 16167–73 | date = May 2000 | pmid = 10748123 | doi = 10.1074/jbc.M909302199 | doi-access = free }}
• {{cite journal | vauthors = Miyagi Y, Yamashita T, Fukaya M, Sonoda T, Okuno T, Yamada K, Watanabe M, Nagashima Y, Aoki I, Okuda K, Mishina M, Kawamoto S | title = Delphilin: a novel PDZ and formin homology domain-containing protein that synaptically colocalizes and interacts with glutamate receptor delta 2 subunit | journal = The Journal of Neuroscience | volume = 22 | issue = 3 | pages = 803–14 | date = Feb 2002 | pmid = 11826110 | doi = 10.1523/JNEUROSCI.22-03-00803.2002| pmc = 6758529 | doi-access = free }}
• {{cite journal | vauthors = Ly CD, Roche KW, Lee HK, Wenthold RJ | title = Identification of rat EMAP, a delta-glutamate receptor binding protein | journal = Biochemical and Biophysical Research Communications | volume = 291 | issue = 1 | pages = 85–90 | date = Feb 2002 | pmid = 11829466 | doi = 10.1006/bbrc.2002.6413 | url = https://zenodo.org/record/1229546 }}
• {{cite journal | vauthors = Yue Z, Horton A, Bravin M, DeJager PL, Selimi F, Heintz N | title = A novel protein complex linking the delta 2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice | journal = Neuron | volume = 35 | issue = 5 | pages = 921–33 | date = Aug 2002 | pmid = 12372286 | doi = 10.1016/S0896-6273(02)00861-9 | s2cid = 10534933 | doi-access = free }}
• {{cite journal | vauthors = Kohda K, Kamiya Y, Matsuda S, Kato K, Umemori H, Yuzaki M | title = Heteromer formation of delta2 glutamate receptors with AMPA or kainate receptors | journal = Brain Research. Molecular Brain Research | volume = 110 | issue = 1 | pages = 27–37 | date = Jan 2003 | pmid = 12573530 | doi = 10.1016/S0169-328X(02)00561-2 }}
• {{cite journal | vauthors = Yap CC, Muto Y, Kishida H, Hashikawa T, Yano R | title = PKC regulates the delta2 glutamate receptor interaction with S-SCAM/MAGI-2 protein | journal = Biochemical and Biophysical Research Communications | volume = 301 | issue = 4 | pages = 1122–8 | date = Feb 2003 | pmid = 12589829 | doi = 10.1016/S0006-291X(03)00070-6 }}
• {{cite journal | vauthors = Sonoda T, Mochizuki C, Yamashita T, Watanabe-Kaneko K, Miyagi Y, Shigeri Y, Yazama F, Okuda K, Kawamoto S | title = Binding of glutamate receptor delta2 to its scaffold protein, Delphilin, is regulated by PKA | journal = Biochemical and Biophysical Research Communications | volume = 350 | issue = 3 | pages = 748–52 | date = Nov 2006 | pmid = 17027646 | doi = 10.1016/j.bbrc.2006.09.109 }}

{{Refend}}

{{Ligand-gated ion channels}}

Category:Ionotropic glutamate receptors