GRID2 explained

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 in the absence of pre-synaptic connections.[5] Glycine and D-serine can open the channel in GluD2 when bound to cerebellin-1 and neurexin-1β.[11] 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[12] whereas a homozygous biallelic deletion leads to a syndrome of cerebellar ataxia with marked developmental delay, pyramidal tract involvement[13] and tonic upgaze,[14] 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.[15] [16] 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.[17]

Interactions

GRID2 has been shown to interact with GOPC,[18] GRIK2,[19] PTPN4[20] and GRIA1.[19] 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.[21] [22] [23] [24] [25] 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.[26]

See also

Further reading

Notes and References

  1. Web site: Entrez Gene: GRID2 glutamate receptor, ionotropic, delta 2.
  2. Hu W, Zuo J, De Jager PL, Heintz N . The human glutamate receptor delta 2 gene (GRID2) maps to chromosome 4q22 . Genomics . 47 . 1 . 143–5 . Jan 1998 . 9465309 . 10.1006/geno.1997.5108 .
  3. Lomeli H, Sprengel R, Laurie DJ, Köhr G, Herb A, Seeburg PH, Wisden W . The rat delta-1 and delta-2 subunits extend the excitatory amino acid receptor family . FEBS Letters . 315 . 3 . 318–22 . Jan 1993 . 8422924 . 10.1016/0014-5793(93)81186-4 . 43024586 . free .
  4. Naur P, Hansen KB, Kristensen AS, Dravid SM, Pickering DS, Olsen L, Vestergaard B, Egebjerg J, Gajhede M, Traynelis SF, Kastrup JS . Ionotropic glutamate-like receptor delta2 binds D-serine and glycine . Proc. Natl. Acad. Sci. USA . 104 . 35 . 14116–14121 . August 2007 . 17715062 . 10.1073/pnas.0703718104 . 1955790. 2007PNAS..10414116N . free .
  5. Hansen KB, Naur P, Kurtkaya NL, Kristensen AS, Gajhede M, Kastrup JS, Traynelis SF . 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 . Jan 2009 . 19176800 . 10.1523/JNEUROSCI.4081-08.2009 . 2806602.
  6. Araki K, Meguro H, Kushiya E, Takayama C, Inoue Y, Mishina M . Selective expression of the glutamate receptor channel delta 2 subunit in cerebellar Purkinje cells . Biochemical and Biophysical Research Communications . 197 . 3 . 1267–76 . Dec 1993 . 7506541 . 10.1006/bbrc.1993.2614 .
  7. Yuzaki M . Cerebellar LTD vs. motor learning-lessons learned from studying GluD2 . Neural Networks . 47 . 36–41 . Nov 2013 . 22840919 . 10.1016/j.neunet.2012.07.001 .
  8. Matsuda K, Yuzaki M . Cbln1 and the δ2 glutamate receptor--an orphan ligand and an orphan receptor find their partners . Cerebellum . 11 . 1 . 78–84 . Mar 2012 . 20535596 . 10.1007/s12311-010-0186-5 . 16612844 .
  9. Kakegawa W, Miyazaki T, Emi K, Matsuda K, Kohda K, Motohashi J, Mishina M, Kawahara S, Watanabe M, Yuzaki M . Differential regulation of synaptic plasticity and cerebellar motor learning by the C-terminal PDZ-binding motif of GluRdelta2 . J. Neurosci. . 28 . 6 . 1460–1468 . February 2008 . 18256267 . 10.1523/JNEUROSCI.2553-07.2008 . 6671576 .
  10. Kakegawa W, Miyoshi Y, Hamase K, Matsuda S, Matsuda K, Kohda K, Emi K, Motohashi J, Konno R, Zaitsu K, Yuzaki M . D-serine regulates cerebellar LTD and motor coordination through the δ2 glutamate receptor . Nat. Neurosci. . 14 . 5 . 603–611 . May 2011 . 21460832 . 10.1038/nn.2791 . 17507539 .
  11. Carrillo. Elisa. Gonzalez. Cuauhtemoc U.. Berka. Vladimir. Jayaraman. Vasanthi. 2021-12-24. Delta glutamate receptors are functional glycine- and ᴅ-serine–gated cation channels in situ. Science Advances. en. 7. 52. eabk2200. 10.1126/sciadv.abk2200. 2375-2548. 8694607. 34936451. 2021SciA....7.2200C .
  12. Maier A, Klopocki E, Horn D, Tzschach A, Holm T, Meyer R, Meyer T . De novo partial deletion in GRID2 presenting with complicated spastic paraplegia . Muscle & Nerve . 49 . 2 . 289–92 . Feb 2014 . 24122788 . 10.1002/mus.24096 . 26359325 .
  13. Utine GE, Haliloğlu G, Salanci B, Çetinkaya A, Kiper PÖ, Alanay Y, Aktas D, Boduroğlu K, Alikaşifoğlu M . A homozygous deletion in GRID2 causes a human phenotype with cerebellar ataxia and atrophy . Journal of Child Neurology . 28 . 7 . 926–32 . Jul 2013 . 23611888 . 10.1177/0883073813484967 . 206550612 .
  14. 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 . Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans . Neurology . 81 . 16 . 1378–86 . Oct 2013 . 24078737 . 10.1212/WNL.0b013e3182a841a3 . 3806907.
  15. Lalonde R, Botez MI, Joyal CC, Caumartin M . Motor abnormalities in lurcher mutant mice . Physiology & Behavior . 51 . 3 . 523–5 . Mar 1992 . 1523229 . 10.1016/0031-9384(92)90174-Z . 33424240 .
  16. Zuo J, De Jager PL, Takahashi KA, Jiang W, Linden DJ, Heintz N . Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene . Nature . 388 . 6644 . 769–73 . Aug 1997 . 9285588 . 10.1038/42009 . 1997Natur.388..769Z . 4431774 . free .
  17. Williams K, Dattilo M, Sabado TN, Kashiwagi K, Igarashi K . Pharmacology of delta2 glutamate receptors: effects of pentamidine and protons . The Journal of Pharmacology and Experimental Therapeutics . 305 . 2 . 740–8 . May 2003 . 12606689 . 10.1124/jpet.102.045799 . 83540259 .
  18. Yue Z, Horton A, Bravin M, DeJager PL, Selimi F, Heintz N . A novel protein complex linking the delta 2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice . Neuron . 35 . 5 . 921–33 . Aug 2002 . 12372286 . 10.1016/S0896-6273(02)00861-9 . 10534933 . free .
  19. Kohda K, Kamiya Y, Matsuda S, Kato K, Umemori H, Yuzaki M . Heteromer formation of delta2 glutamate receptors with AMPA or kainate receptors . Brain Research. Molecular Brain Research . 110 . 1 . 27–37 . Jan 2003 . 12573530 . 10.1016/S0169-328X(02)00561-2 .
  20. Hironaka K, Umemori H, Tezuka T, Mishina M, Yamamoto T . The protein-tyrosine phosphatase PTPMEG interacts with glutamate receptor delta 2 and epsilon subunits . The Journal of Biological Chemistry . 275 . 21 . 16167–73 . May 2000 . 10748123 . 10.1074/jbc.M909302199 . free .
  21. Hess DC, Hill WD, Carroll JE, Borlongan CV . Do bone marrow cells generate neurons? . Archives of Neurology . 61 . 4 . 483–5 . Apr 2004 . 15096394 . 10.1001/archneur.61.4.483 . free .
  22. Weimann JM, Johansson CB, Trejo A, Blau HM . Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant . Nature Cell Biology . 5 . 11 . 959–66 . Nov 2003 . 14562057 . 10.1038/ncb1053 . 33685652 .
  23. Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A . Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes . Nature . 425 . 6961 . 968–73 . Oct 2003 . 14555960 . 10.1038/nature02069 . 2003Natur.425..968A . 2027.42/62789 . 4394453 . free .
  24. Felizola SJ, Katsu K, Ise K, Nakamura Y, Arai Y, Satoh F, Sasano H . 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 . May 2015 . 25861052 . 10.1007/s12022-015-9366-7 . 27271366 .
  25. Kemp K, Wilkins A, Scolding N . Cell fusion in the brain: two cells forward, one cell back . Acta Neuropathologica . 128 . 5 . 629–38 . Nov 2014 . 24899142 . 10.1007/s00401-014-1303-1 . 4201757.
  26. Berenova M, Mandakova P, Sima P, Slipka J, Vozeh F, Kocova J, Cervinkova M, Sykora J . Morphology of Adrenal Gland and Lymph Organs is Impaired in Neurodeficient Lurcher Mutant Mice.. Acta Vet. Brno . 71 . 23–28 . 2002 . 10.2754/avb200271010023 . free .

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