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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{About|a protein|a racing video game|Grid 2}}
{{PBB_Controls
{{Infobox_gene}}
| update_page = yes
'''Glutamate receptor, ionotropic, delta 2''', also known as '''GluD2''', '''GluRδ2''', or '''δ<sub>2</sub>''', is a [[protein]] that in humans is encoded by the ''GRID2'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: GRID2 glutamate receptor, ionotropic, delta 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2895| accessdate = }}</ref><ref name="pmid9465309">{{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 }}</ref> This protein together with [[GRID1|GluD1]] belongs to the delta receptor subtype of [[ionotropic glutamate receptor]]s. They possess 14–24% [[DNA sequence|sequence]] [[homology (biology)|homology]] with [[AMPA receptor|AMPA]], [[Kainate receptor|kainate]], and [[NMDA receptor|NMDA]] subunits, but, despite their name, do not actually bind [[glutamate]] or various other glutamate agonists.<ref name="pmid8422924">{{cite journal | vauthors = Lomeli H, Sprengel R, Laurie DJ, Köhr G, Herb A, Seeburg PH, Wisden W | title = The rat delta-1 and delta-2 subunits extend the excitatory amino acid receptor family | journal = FEBS Letters | volume = 315 | issue = 3 | pages = 318–22 | date = Jan 1993 | pmid = 8422924 | doi = 10.1016/0014-5793(93)81186-4 | url = http://linkinghub.elsevier.com/retrieve/pii/0014-5793(93)81186-4 }}</ref>
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
delta iGluRs have long been considered [[orphan receptor]]s as their [[endogenous]] [[ligand]] was unknown. They are now believed to bind glycine and D-serine but these do not result in channel opening.<ref>{{cite journal | vauthors = Naur P, Hansen KB, Kristensen AS, Dravid SM, Pickering DS, Olsen L, Vestergaard B, Egebjerg J, Gajhede M, Traynelis SF, Kastrup JS | title = Ionotropic glutamate-like receptor delta2 binds D-serine and glycine | journal = Proc. Natl. Acad. Sci. USA | volume = 104 | issue = 35 | pages = 14116–14121 | date = August 2007 | pmid = 17715062 | doi = 10.1073/pnas.0703718104 | url = http://www.pnas.org/content/104/35/14116.long | pmc=1955790}}</ref><ref name="pmid19176800">{{cite journal | vauthors = Hansen KB, Naur P, Kurtkaya NL, Kristensen AS, Gajhede M, Kastrup JS, Traynelis SF | title = Modulation of the dimer interface at ionotropic glutamate-like receptor delta2 by D-serine and extracellular calcium | journal = The Journal of Neuroscience | volume = 29 | issue = 4 | pages = 907–17 | date = Jan 2009 | pmid = 19176800 | doi = 10.1523/JNEUROSCI.4081-08.2009 | url = http://www.jneurosci.org/content/29/4/907.long | pmc=2806602}}</ref>
{{GNF_Protein_box
| image =
| image_source = 
| PDB =
| Name = Glutamate receptor, ionotropic, delta 2
| HGNCid = 4576
| Symbol = GRID2
| AltSymbols =; MGC117022; MGC117023; MGC117024
| OMIM = 602368
| ECnumber =
| Homologene = 74399
| MGIid = 95813
| GeneAtlas_image1 = PBB_GE_GRID2_221364_at_tn.png
| Function = {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0004970 |text = ionotropic glutamate receptor activity}} {{GNF_GO|id=GO:0005216 |text = ion channel activity}} {{GNF_GO|id=GO:0005234 |text = extracellular-glutamate-gated ion channel activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}}
| Component = {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0019717 |text = synaptosome}} {{GNF_GO|id=GO:0045211 |text = postsynaptic membrane}}
| Process = {{GNF_GO|id=GO:0006811 |text = ion transport}} {{GNF_GO|id=GO:0007215 |text = glutamate signaling pathway}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 2895
    | Hs_Ensembl = ENSG00000152208
    | Hs_RefseqProtein = NP_001501
    | Hs_RefseqmRNA = NM_001510
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 4
    | Hs_GenLoc_start = 93444831
    | Hs_GenLoc_end = 94912672
    | Hs_Uniprot = O43424
    | Mm_EntrezGene = 14804
    | Mm_Ensembl = ENSMUSG00000071424
    | Mm_RefseqmRNA = XM_989862
    | Mm_RefseqProtein = XP_994956
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 6
    | Mm_GenLoc_start = 63186435
    | Mm_GenLoc_end = 64595857
    | Mm_Uniprot = Q8CCJ1
  }}
}}
'''Glutamate receptor, ionotropic, delta 2''', also known as '''GRID2''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: GRID2 glutamate receptor, ionotropic, delta 2| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2895| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{PBB_Summary
| section_title =  
| summary_text = Human glutamate receptor delta-2 (GRID2) is a relatively new member of the family of ionotropic glutamate receptors which are the predominant excitatory neurotransmitter receptors in the mammalian brain.  GRID2 is a predicted 1,007 amino acid protein that shares 97% identity with the mouse homolog which is expressed selectively in cerebellar Purkinje cells.  A point mutation in mouse GRID2, associated with the phenotype named 'lurcher', in the heterozygous state leads to ataxia resulting from selective, cell-autonomous apoptosis of cerebellar Purkinje cells during postnatal development. Mice homozygous for this mutation die shortly after birth from massive loss of mid- and hindbrain neurons during late embryogenesis.  This strongly suggests a role for GRID2 in neuronal apoptotic death.<ref name="entrez">{{cite web | title = Entrez Gene: GRID2 glutamate receptor, ionotropic, delta 2| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2895| accessdate = }}</ref>
}}


==References==
GluD2-containing receptors are selectively/predominantly expressed in [[Purkinje cell]]s in the [[cerebellum]]<ref name="pmid8422924"/><ref name="pmid7506541">{{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 | url = http://linkinghub.elsevier.com/retrieve/pii/S0006-291X(83)72614-8 }}</ref> where they play a key role in [[synaptogenesis]], [[synaptic plasticity]], and [[motor coordination]].<ref name="pmid22840919">{{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 | url = http://www.sciencedirect.com/science/article/pii/S0893608012001797 }}</ref>
{{reflist|2}}
==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal | author=Araki K, Meguro H, Kushiya E, ''et al.'' |title=Selective expression of the glutamate receptor channel delta 2 subunit in cerebellar Purkinje cells. |journal=Biochem. Biophys. Res. Commun. |volume=197 |issue= 3 |pages= 1267-76 |year= 1994 |pmid= 7506541 |doi= 10.1006/bbrc.1993.2614 }}
*{{cite journal  | author=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 |year= 1998 |pmid= 9465309 |doi= 10.1006/geno.1997.5108 }}
*{{cite journal  | author= |title=Toward a complete human genome sequence. |journal=Genome Res. |volume=8 |issue= 11 |pages= 1097-108 |year= 1999 |pmid= 9847074 |doi=  }}
*{{cite journal  | author=Roche KW, Ly CD, Petralia RS, ''et al.'' |title=Postsynaptic density-93 interacts with the delta2 glutamate receptor subunit at parallel fiber synapses. |journal=J. Neurosci. |volume=19 |issue= 10 |pages= 3926-34 |year= 1999 |pmid= 10234023 |doi=  }}
*{{cite journal  | author=Hironaka K, Umemori H, Tezuka T, ''et al.'' |title=The protein-tyrosine phosphatase PTPMEG interacts with glutamate receptor delta 2 and epsilon subunits. |journal=J. Biol. Chem. |volume=275 |issue= 21 |pages= 16167-73 |year= 2000 |pmid= 10748123 |doi= 10.1074/jbc.M909302199 }}
*{{cite journal | author=Miyagi Y, Yamashita T, Fukaya M, ''et al.'' |title=Delphilin: a novel PDZ and formin homology domain-containing protein that synaptically colocalizes and interacts with glutamate receptor delta 2 subunit. |journal=J. Neurosci. |volume=22 |issue= 3 |pages= 803-14 |year= 2002 |pmid= 11826110 |doi=  }}
*{{cite journal  | author=Ly CD, Roche KW, Lee HK, Wenthold RJ |title=Identification of rat EMAP, a delta-glutamate receptor binding protein. |journal=Biochem. Biophys. Res. Commun. |volume=291 |issue= 1 |pages= 85-90 |year= 2002 |pmid= 11829466 |doi= 10.1006/bbrc.2002.6413 }}
*{{cite journal  | author=Yue Z, Horton A, Bravin M, ''et al.'' |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 |year= 2002 |pmid= 12372286 |doi=  }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal  | author=Kohda K, Kamiya Y, Matsuda S, ''et al.'' |title=Heteromer formation of delta2 glutamate receptors with AMPA or kainate receptors. |journal=Brain Res. Mol. Brain Res. |volume=110 |issue= 1 |pages= 27-37 |year= 2003 |pmid= 12573530 |doi=  }}
*{{cite journal  | author=Yap CC, Muto Y, Kishida H, ''et al.'' |title=PKC regulates the delta2 glutamate receptor interaction with S-SCAM/MAGI-2 protein. |journal=Biochem. Biophys. Res. Commun. |volume=301 |issue= 4 |pages= 1122-8 |year= 2003 |pmid= 12589829 |doi=  }}
*{{cite journal  | author=Sonoda T, Mochizuki C, Yamashita T, ''et al.'' |title=Binding of glutamate receptor delta2 to its scaffold protein, Delphilin, is regulated by PKA. |journal=Biochem. Biophys. Res. Commun. |volume=350 |issue= 3 |pages= 748-52 |year= 2006 |pmid= 17027646 |doi= 10.1016/j.bbrc.2006.09.109 }}
}}
{{refend}}


{{protein-stub}}
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.<ref name="pmid22840919"/><ref>{{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 }}</ref>
{{WikiDoc Sources}}
 
The main functions of GluD2 in synaptic plasticity are carried out by its intracellular C-terminus.<ref>{{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 | url = http://www.jneurosci.org/content/28/6/1460.long}}</ref> This is regulated by D-serine,<ref>{{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 | url = http://www.nature.com/neuro/journal/v14/n5/full/nn.2791.html}}</ref> which binds to the ligand-binding domain and results in changes in the structure of GluD2 without opening the channel.<ref name="pmid19176800"/> These changes may signal up to the N-terminal domain or down to the C-terminal domain to alter [[protein-protein interactions]].
 
== Pathology ==
 
A heterozygous deletion in GRID2 in humans causes a complicated spastic paraplegia with ataxia, frontotemporal dementia, and lower motor neuron involvement<ref name="pmid24122788">{{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 }}</ref> whereas a homozygous biallelic deletion leads to a syndrome of cerebellar ataxia with marked developmental delay, pyramidal tract involvement<ref>{{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 }}</ref> and tonic upgaze,<ref>{{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}}</ref> 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.<ref name="pmid1523229">{{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 }}</ref> Mice homozygous for this mutation die shortly after birth from massive loss of mid- and hindbrain neurons during late [[embryogenesis]].
 
== Ligands ==
 
[[9-Aminoacridine]], [[9-tetrahydroaminoacridine]], [[N1-dansyl-spermine]], [[N1-dansyl-spermidine]], and [[pentamidine]] have been shown to act as [[receptor antagonist|antagonist]]s of δ<sub>2</sub>-containing receptors.<ref name="pmid12606689">{{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 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12606689 }}</ref>
 
== Interactions ==
 
GRID2 has been shown to [[Protein-protein interaction|interact]] with [[GOPC]],<ref name=pmid12372286>{{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 }}</ref> [[GRIK2]],<ref name=pmid12573530>{{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 }}</ref> [[PTPN4]]<ref name=pmid10748123>{{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 }}</ref> and [[GRIA1]].<ref name=pmid12573530/> 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 [[Cerebellum|cerebellar]] [[Purkinje cell|Purkinje neurons]] in humans.<ref name= "Hess et al">{{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_Do_bone_marrow_cells_generate_neurons }}</ref><ref name= "Weimann et al">{{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 | url = https://www.researchgate.net/publication/9048544_Stable_reprogrammed_heterokaryons_form_spontaneously_in_Purkinje_neurons_after_bone_marrow_transplant }}</ref><ref name= "Alvarez-Dolado">{{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 | url = https://www.researchgate.net/publication/9053693_Fusion_of_bone-marrow-derived_cells_with_Purkinje_neurons_cardiomyocytes_and_hepatocytes }}</ref><ref name= "vpreb3">{{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 | url = https://www.researchgate.net/publication/274075697_Pre-B_lymphocyte_protein_3_%28VPREB3%29_expression_in_the_adrenal_cortex_precedent_for_non-immunological_roles_in_normal_and_neoplastic_human_tissues }}</ref><ref name= "Kemp et al">{{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 | url = https://www.researchgate.net/publication/262884941_Cell_fusion_in_the_brain_two_cells_forward_one_cell_back | pmc=4201757}}</ref> Morphological studies conducted in GRID2-[[Knockout mouse|knockout mice]] suggest that GRID2 may be present in [[lymphocyte]]s as well as in the [[adrenal cortex]], however further studies must be conducted to confirm these claims.<ref name= "vpreb3" /><ref name= "Berenova">{{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 |issue= |pages= 23–28 |year= 2002 |doi= 10.2754/avb200271010023 |pmid= | url= https://www.researchgate.net/publication/254241098_Morphology_of_Adrenal_Gland_and_Lymph_Organs_is_Impaired_in_Neurodeficient_Lurcher_Mutant_Mice}}</ref>
 
== See also ==
* [[GRID1]]
 
== References ==
{{Reflist|2}}
 
== Further reading ==
{{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 | vauthors =  | 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 }}
* {{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 =  }}
* {{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 }}
* {{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 =  }}
* {{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 }}
* {{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 }}
* {{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]]

Revision as of 03:16, 27 October 2017

This article is about a protein. For a racing video game, see Grid 2.
VALUE_ERROR (nil)
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Glutamate receptor, ionotropic, delta 2, also known as GluD2, GluRδ2, or δ2, is a protein that in humans is encoded by the GRID2 gene.[1][2] This protein together with GluD1 belongs to the delta receptor subtype of ionotropic glutamate receptors. They possess 14–24% sequence homology with AMPA, kainate, and NMDA subunits, but, despite their name, do not actually bind glutamate or various other glutamate agonists.[3]

delta iGluRs have long been considered orphan receptors as their endogenous ligand was unknown. They are now believed to bind glycine and D-serine but these do not result in channel opening.[4][5]

Function

GluD2-containing receptors are selectively/predominantly expressed in Purkinje cells in the cerebellum[3][6] where they play a key role in synaptogenesis, synaptic plasticity, and motor coordination.[7]

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.[7][8]

The main functions of GluD2 in synaptic plasticity are carried out by its intracellular C-terminus.[9] This is regulated by D-serine,[10] which binds to the ligand-binding domain and results in changes in the structure of GluD2 without opening the channel.[5] These changes may signal up to the N-terminal domain or down to the C-terminal domain to alter protein-protein interactions.

Pathology

A heterozygous deletion in GRID2 in humans causes a complicated spastic paraplegia with ataxia, frontotemporal dementia, and lower motor neuron involvement[11] whereas a homozygous biallelic deletion leads to a syndrome of cerebellar ataxia with marked developmental delay, pyramidal tract involvement[12] and tonic upgaze,[13] 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.[14] Mice homozygous for this mutation die shortly after birth from massive loss of mid- and hindbrain neurons during late embryogenesis.

Ligands

9-Aminoacridine, 9-tetrahydroaminoacridine, N1-dansyl-spermine, N1-dansyl-spermidine, and pentamidine have been shown to act as antagonists of δ2-containing receptors.[15]

Interactions

GRID2 has been shown to interact with GOPC,[16] GRIK2,[17] PTPN4[18] and GRIA1.[17] 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.[19][20][21][22][23] 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.[22][24]

See also

References

  1. ↑ "Entrez Gene: GRID2 glutamate receptor, ionotropic, delta 2".
  2. ↑ Hu W, Zuo J, De Jager PL, Heintz N (Jan 1998). "The human glutamate receptor delta 2 gene (GRID2) maps to chromosome 4q22". Genomics. 47 (1): 143–5. doi:10.1006/geno.1997.5108. PMID 9465309.
  3. ↑ 3.0 3.1 Lomeli H, Sprengel R, Laurie DJ, Köhr G, Herb A, Seeburg PH, Wisden W (Jan 1993). "The rat delta-1 and delta-2 subunits extend the excitatory amino acid receptor family". FEBS Letters. 315 (3): 318–22. doi:10.1016/0014-5793(93)81186-4. PMID 8422924.
  4. ↑ Naur P, Hansen KB, Kristensen AS, Dravid SM, Pickering DS, Olsen L, Vestergaard B, Egebjerg J, Gajhede M, Traynelis SF, Kastrup JS (August 2007). "Ionotropic glutamate-like receptor delta2 binds D-serine and glycine". Proc. Natl. Acad. Sci. USA. 104 (35): 14116–14121. doi:10.1073/pnas.0703718104. PMC 1955790. PMID 17715062.
  5. ↑ 5.0 5.1 Hansen KB, Naur P, Kurtkaya NL, Kristensen AS, Gajhede M, Kastrup JS, Traynelis SF (Jan 2009). "Modulation of the dimer interface at ionotropic glutamate-like receptor delta2 by D-serine and extracellular calcium". The Journal of Neuroscience. 29 (4): 907–17. doi:10.1523/JNEUROSCI.4081-08.2009. PMC 2806602. PMID 19176800.
  6. ↑ Araki K, Meguro H, Kushiya E, Takayama C, Inoue Y, Mishina M (Dec 1993). "Selective expression of the glutamate receptor channel delta 2 subunit in cerebellar Purkinje cells". Biochemical and Biophysical Research Communications. 197 (3): 1267–76. doi:10.1006/bbrc.1993.2614. PMID 7506541.
  7. ↑ 7.0 7.1 Yuzaki M (Nov 2013). "Cerebellar LTD vs. motor learning-lessons learned from studying GluD2". Neural Networks. 47: 36–41. doi:10.1016/j.neunet.2012.07.001. PMID 22840919.
  8. ↑ Matsuda K, Yuzaki M (Mar 2012). "Cbln1 and the δ2 glutamate receptor--an orphan ligand and an orphan receptor find their partners". Cerebellum. 11 (1): 78–84. doi:10.1007/s12311-010-0186-5. PMID 20535596.
  9. ↑ Kakegawa W, Miyazaki T, Emi K, Matsuda K, Kohda K, Motohashi J, Mishina M, Kawahara S, Watanabe M, Yuzaki M (February 2008). "Differential regulation of synaptic plasticity and cerebellar motor learning by the C-terminal PDZ-binding motif of GluRdelta2". J. Neurosci. 28 (6): 1460–1468. doi:10.1523/JNEUROSCI.2553-07.2008. PMID 18256267.
  10. ↑ Kakegawa W, Miyoshi Y, Hamase K, Matsuda S, Matsuda K, Kohda K, Emi K, Motohashi J, Konno R, Zaitsu K, Yuzaki M (May 2011). "D-serine regulates cerebellar LTD and motor coordination through the δ2 glutamate receptor". Nat. Neurosci. 14 (5): 603–611. doi:10.1038/nn.2791. PMID 21460832.
  11. ↑ Maier A, Klopocki E, Horn D, Tzschach A, Holm T, Meyer R, Meyer T (Feb 2014). "De novo partial deletion in GRID2 presenting with complicated spastic paraplegia". Muscle & Nerve. 49 (2): 289–92. doi:10.1002/mus.24096. PMID 24122788.
  12. ↑ Utine GE, Haliloğlu G, Salanci B, Çetinkaya A, Kiper PÖ, Alanay Y, Aktas D, Boduroğlu K, Alikaşifoğlu M (Jul 2013). "A homozygous deletion in GRID2 causes a human phenotype with cerebellar ataxia and atrophy". Journal of Child Neurology. 28 (7): 926–32. doi:10.1177/0883073813484967. PMID 23611888.
  13. ↑ 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 (Oct 2013). "Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans". Neurology. 81 (16): 1378–86. doi:10.1212/WNL.0b013e3182a841a3. PMC 3806907. PMID 24078737.
  14. ↑ Lalonde R, Botez MI, Joyal CC, Caumartin M (Mar 1992). "Motor abnormalities in lurcher mutant mice". Physiology & Behavior. 51 (3): 523–5. doi:10.1016/0031-9384(92)90174-Z. PMID 1523229.
  15. ↑ Williams K, Dattilo M, Sabado TN, Kashiwagi K, Igarashi K (May 2003). "Pharmacology of delta2 glutamate receptors: effects of pentamidine and protons". The Journal of Pharmacology and Experimental Therapeutics. 305 (2): 740–8. doi:10.1124/jpet.102.045799. PMID 12606689.
  16. ↑ Yue Z, Horton A, Bravin M, DeJager PL, Selimi F, Heintz N (Aug 2002). "A novel protein complex linking the delta 2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice". Neuron. 35 (5): 921–33. doi:10.1016/S0896-6273(02)00861-9. PMID 12372286.
  17. ↑ 17.0 17.1 Kohda K, Kamiya Y, Matsuda S, Kato K, Umemori H, Yuzaki M (Jan 2003). "Heteromer formation of delta2 glutamate receptors with AMPA or kainate receptors". Brain Research. Molecular Brain Research. 110 (1): 27–37. doi:10.1016/S0169-328X(02)00561-2. PMID 12573530.
  18. ↑ Hironaka K, Umemori H, Tezuka T, Mishina M, Yamamoto T (May 2000). "The protein-tyrosine phosphatase PTPMEG interacts with glutamate receptor delta 2 and epsilon subunits". The Journal of Biological Chemistry. 275 (21): 16167–73. doi:10.1074/jbc.M909302199. PMID 10748123.
  19. ↑ Hess DC, Hill WD, Carroll JE, Borlongan CV (Apr 2004). "Do bone marrow cells generate neurons?". Archives of Neurology. 61 (4): 483–5. doi:10.1001/archneur.61.4.483. PMID 15096394.
  20. ↑ Weimann JM, Johansson CB, Trejo A, Blau HM (Nov 2003). "Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant". Nature Cell Biology. 5 (11): 959–66. doi:10.1038/ncb1053. PMID 14562057.
  21. ↑ Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A (Oct 2003). "Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes". Nature. 425 (6961): 968–73. doi:10.1038/nature02069. PMID 14555960.
  22. ↑ 22.0 22.1 Felizola SJ, Katsu K, Ise K, Nakamura Y, Arai Y, Satoh F, Sasano H (May 2015). "Pre-B Lymphocyte Protein 3 (VPREB3) Expression in the Adrenal Cortex: Precedent for non-Immunological Roles in Normal and Neoplastic Human Tissues". Endocrine Pathology. 26 (2): 119–28. doi:10.1007/s12022-015-9366-7. PMID 25861052.
  23. ↑ Kemp K, Wilkins A, Scolding N (Nov 2014). "Cell fusion in the brain: two cells forward, one cell back". Acta Neuropathologica. 128 (5): 629–38. doi:10.1007/s00401-014-1303-1. PMC 4201757. PMID 24899142.
  24. ↑ Berenova M, Mandakova P, Sima P, Slipka J, Vozeh F, Kocova J, Cervinkova M, Sykora J (2002). "Morphology of Adrenal Gland and Lymph Organs is Impaired in Neurodeficient Lurcher Mutant Mice". Acta Vet. Brno. 71: 23–28. doi:10.2754/avb200271010023.

Further reading

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