GRID2

Glutamate receptor, ionotropic, delta 2, also known as GluD2, GluRδ2, or δ₂, is a protein that in humans is encoded by the GRID2 gene.[5][6] 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.[7]

GRID2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 5KCA, 5KC8
Identifiers
Aliases	GRID2, GluD2, SCAR18, glutamate ionotropic receptor delta type subunit 2
External IDs	OMIM: 602368 MGI: 95813 HomoloGene: 74399 GeneCards: GRID2
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4q22.1-q22.2 Start 92,303,966 bp[1] End 93,810,157 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6 C1|6 29.77 cM Start 63,255,876 bp[2] End 64,704,323 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • glutamate receptor activity • PDZ domain binding • scaffold protein binding • ion channel activity • ionotropic glutamate receptor activity • extracellular-glutamate-gated ion channel activity • GO:0001948 protein binding • signaling receptor activity • transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential Cellular component • integral component of membrane • postsynaptic membrane • membrane • cell membrane • dendritic spine • synapse • integral component of plasma membrane • cell junction • ionotropic glutamate receptor complex • somatodendritic compartment • parallel fiber to Purkinje cell synapse • glutamatergic synapse • integral component of postsynaptic density membrane Biological process • glutamate receptor signaling pathway • heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules • regulation of neuron projection development • synaptic transmission, glutamatergic • regulation of neuron apoptotic process • ion transport • cellular protein localization • ion transmembrane transport • ionotropic glutamate receptor signaling pathway • excitatory postsynaptic potential • cerebellar granule cell differentiation • prepulse inhibition • positive regulation of synapse assembly • positive regulation of long term synaptic depression • excitatory synapse assembly • regulation of postsynaptic density assembly • modulation of chemical synaptic transmission Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	2895	14804
Ensembl	ENSG00000152208	ENSMUSG00000071424
UniProt	O43424	Q61625
RefSeq (mRNA)	NM_001286838 NM_001510	NM_008167 NM_001370966
RefSeq (protein)	NP_001273767 NP_001501	NP_032193 NP_001357895
Location (UCSC)	Chr 4: 92.3 – 93.81 Mb	Chr 6: 63.26 – 64.7 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[8][9]

Function

GluD2-containing receptors are selectively/predominantly expressed in Purkinje cells in the cerebellum[7][10] where they play a key role in synaptogenesis, synaptic plasticity, and motor coordination.[11]

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.[11][12]

The main functions of GluD2 in synaptic plasticity are carried out by its intracellular C-terminus.[13] This is regulated by D-serine,[14] which binds to the ligand-binding domain and results in changes in the structure of GluD2 without opening the channel.[9] 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[15] whereas a homozygous biallelic deletion leads to a syndrome of cerebellar ataxia with marked developmental delay, pyramidal tract involvement[16] and tonic upgaze,[17] 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.[18][19] 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.[20]

Interactions

GRID2 has been shown to interact with GOPC,[21] GRIK2,[22] PTPN4[23] and GRIA1.[22] 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.[24][25][26][27][28] 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.[27][29]

See also

• GRID1

References

1. GRCh38: Ensembl release 89: ENSG00000152208 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000071424 - 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. "Entrez Gene: GRID2 glutamate receptor, ionotropic, delta 2".
6. 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.
7. 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. S2CID 43024586.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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. S2CID 16612844.
13. 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. PMC 6671576. PMID 18256267.
14. 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. S2CID 17507539.
15. 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. S2CID 26359325.
16. 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. S2CID 206550612.
17. 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.
18. 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. S2CID 33424240.
19. Zuo J, De Jager PL, Takahashi KA, Jiang W, Linden DJ, Heintz N (Aug 1997). "Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene". Nature. 388 (6644): 769–73. doi:10.1038/42009. PMID 9285588. S2CID 4431774.
20. 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. S2CID 83540259.
21. 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. S2CID 10534933.
22. 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.
23. 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.
24. 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.
25. 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. S2CID 33685652.
26. 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. hdl:2027.42/62789. PMID 14555960. S2CID 4394453.
27. 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. S2CID 27271366.
28. 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.
29. 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.
• Sanger Centre, The; Washington University Genome Sequencing Cente, The (Nov 1998). "Toward a complete human genome sequence". Genome Research. 8 (11): 1097–108. 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. doi:10.1523/JNEUROSCI.19-10-03926.1999. PMC 6782719. 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. doi:10.1523/JNEUROSCI.22-03-00803.2002. PMC 6758529. 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. S2CID 10534933.
• 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.