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RefSeq (mRNA)



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Glutamate receptor 4 is a protein that in humans is encoded by the GRIA4 gene.[1]

This gene is a member of a family of L-glutamate-gated ion channels that mediate fast synaptic excitatory neurotransmission. These channels are also responsive to the glutamate agonist, alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA). Some haplotypes of this gene show a positive association with schizophrenia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[1]


GRIA4 has been shown to interact with CACNG2,[2] GRIP1,[3] PICK1[3] and PRKCG.[4]

RNA editing

Several ion channels and neurotransmitters receptors pre-mRNa are substrates for ADARs. This includes 5 subunits of the glutamate receptor ionotropic AMPA glutamate receptor subunits (Glur2, Glur3, Glur4) and Kainate receptor subunits (Glur5, Glur6). Glutamate-gated ion channels are made up of four subunits per channel. Their function is in the mediation of fast neurotransmission to the brain. The diversity of the subunits is determined, as well as RNA splicing, by RNA editing events of the individual subunits. This give rise to the necessary diversity of the receptors. GluR4 is a gene product of the GRIA4 gene, and its pre-mRNA is subject to RNA editing.


A to I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3, with ADAR 1 and ADAR 2 being the only enzymatically active members.ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR 2 are widely expressed in tissues, while ADAR 3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site with residues usually in a neighboring intron but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS).


The pre-mRNA of this subunit is edited at one position. The R/G editing site is located in exon 13 between the M3 to M4 region. Editing results in a codon change from an Arginine (AGA) to a Glycine (GGA). The location of editing corresponds to a bipartite ligand interaction domain of the receptor.((((((37))))))The R/G site is found at amino acid 769 immediately before the 3-amino-acid-long flip and flop modules introduced by alternative splicing. Flip and Flop forms are present in both edited and nonedited versions of this protein.[5] The editing complimentary sequence (ECS) is found in an intronic sequence close to the exon. The intronic sequence includes a 5' splice site, and the predicted double-stranded region is 30 base pairs in length. The adenosine residue is mismatched in genomically encoded transcript, however this is not the case following editing. Despite similar sequences to the Q/R site of GluR-B, editing this site does not occur in GluR-3 pre-mRNA. Editing results in the targeted adenosine, which is mismatched prior to editing in the double-stranded RNA structure to become matched after editing. The intronic sequence involved contains a 5' donor splice site.[5][6]


Editing also occurs in rat.[5]


Editing of GluR-3 is regulated in rat brain from low levels in embryonic stage to a large increase in editing levels at birth. In humans, 80-90% of GRIA3 transcripts are edited.[5] The absence of the Q/R site editing in this glutamate receptor subunit is due to the absence of necessary intronic sequence required to form a duplex.[7]



Editing results in a codon change from (AGA) to (GGA), an R to a G change at the editing site.[5]


Editing at R/G site allows for faster recovery from desensitisation. Unedited Glu-R at this site have slower recovery rates. Editing, therefore, allows sustained response to rapid stimuli. A crosstalk between editing and splicing is likely to occur here. Editing takes place before splicing. All AMPA receptors occur in flip and flop alternatively spliced variants. AMPA receptors that occur in the Flop form desenstise faster than the flip form.[5] Editing is also thought to affect splicing at this site

See also


  1. 1.0 1.1 "Entrez Gene: GRIA4 glutamate receptor, ionotrophic, AMPA 4".
  2. Chen, L; Chetkovich D M; Petralia R S; Sweeney N T; Kawasaki Y; Wenthold R J; Bredt D S; Nicoll R A (2000). "Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms". Nature. England. 408 (6815): 936–43. doi:10.1038/35050030. ISSN 0028-0836. PMID 11140673.
  3. 3.0 3.1 Hirbec, Hélène; Perestenko Olga; Nishimune Atsushi; Meyer Guido; Nakanishi Shigetada; Henley Jeremy M; Dev Kumlesh K (May 2002). "The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs". J. Biol. Chem. United States. 277 (18): 15221–4. doi:10.1074/jbc.C200112200. ISSN 0021-9258. PMID 11891216.
  4. Correia, Susana Santos; Duarte Carlos Bandeira; Faro Carlos José; Pires Euclides Vieira; Carvalho Ana Luísa (Feb 2003). "Protein kinase C gamma associates directly with the GluR4 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit. Effect on receptor phosphorylation". J. Biol. Chem. United States. 278 (8): 6307–13. doi:10.1074/jbc.M205587200. ISSN 0021-9258. PMID 12471040.
  5. 5.0 5.1 5.2 5.3 5.4 5.5 Lomeli H, Mosbacher J, Melcher T, et al. (December 1994). "Control of kinetic properties of AMPA receptor channels by nuclear RNA editing". Science. 266 (5191): 1709–13. Bibcode:1994Sci...266.1709L. doi:10.1126/science.7992055. PMID 7992055.
  6. Seeburg PH, Higuchi M, Sprengel R (May 1998). "RNA editing of brain glutamate receptor channels: mechanism and physiology". Brain Res. Brain Res. Rev. 26 (2–3): 217–29. doi:10.1016/S0165-0173(97)00062-3. PMID 9651532.
  7. Herb A, Higuchi M, Sprengel R, Seeburg PH (March 1996). "Q/R site editing in kainate receptor GluR5 and GluR6 pre-mRNAs requires distant intronic sequences". Proc. Natl. Acad. Sci. U.S.A. 93 (5): 1875–80. Bibcode:1996PNAS...93.1875H. doi:10.1073/pnas.93.5.1875. PMC 39875. PMID 8700852.

Further reading

  • McNamara JO, Eubanks JH, McPherson JD, et al. (1992). "Chromosomal localization of human glutamate receptor genes". J. Neurosci. 12 (7): 2555–62. PMID 1319477.
  • Hardy M, Younkin D, Tang CM, et al. (1994). "Expression of non-NMDA glutamate receptor channel genes by clonal human neurons". J. Neurochem. 63 (2): 482–9. doi:10.1046/j.1471-4159.1994.63020482.x. PMID 7518497.
  • Roche KW, Raymond LA, Blackstone C, Huganir RL (1994). "Transmembrane topology of the glutamate receptor subunit GluR6". J. Biol. Chem. 269 (16): 11679–82. PMID 8163463.
  • Fletcher EJ, Nutt SL, Hoo KH, et al. (1996). "Cloning, expression and pharmacological characterization of a human glutamate receptor: hGluR4". Recept. Channels. 3 (1): 21–31. PMID 8589990.
  • Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
  • Ripellino JA, Neve RL, Howe JR (1998). "Expression and heteromeric interactions of non-N-methyl-D-aspartate glutamate receptor subunits in the developing and adult cerebellum". Neuroscience. 82 (2): 485–97. doi:10.1016/S0306-4522(97)00296-0. PMID 9466455.
  • Carvalho AL, Kameyama K, Huganir RL (1999). "Characterization of phosphorylation sites on the glutamate receptor 4 subunit of the AMPA receptors". J. Neurosci. 19 (12): 4748–54. PMID 10366608.
  • Chen L, Chetkovich DM, Petralia RS, et al. (2001). "Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms". Nature. 408 (6815): 936–43. doi:10.1038/35050030. PMID 11140673.
  • Hirbec H, Perestenko O, Nishimune A, et al. (2002). "The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs". J. Biol. Chem. 277 (18): 15221–4. doi:10.1074/jbc.C200112200. PMID 11891216.
  • Tomiyama M, Rodríguez-Puertas R, Cortés R, et al. (2002). "Flip and flop splice variants of AMPA receptor subunits in the spinal cord of amyotrophic lateral sclerosis". Synapse. 45 (4): 245–9. doi:10.1002/syn.10098. PMID 12125045.
  • Pasternack A, Coleman SK, Jouppila A, et al. (2003). "Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor channels lacking the N-terminal domain". J. Biol. Chem. 277 (51): 49662–7. doi:10.1074/jbc.M208349200. PMID 12393905.
  • Correia SS, Duarte CB, Faro CJ, et al. (2003). "Protein kinase C gamma associates directly with the GluR4 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit. Effect on receptor phosphorylation". J. Biol. Chem. 278 (8): 6307–13. doi:10.1074/jbc.M205587200. PMID 12471040.
  • Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
  • Makino C, Fujii Y, Kikuta R, et al. (2003). "Positive association of the AMPA receptor subunit GluR4 gene (GRIA4) haplotype with schizophrenia: linkage disequilibrium mapping using SNPs evenly distributed across the gene region". Am. J. Med. Genet. B Neuropsychiatr. Genet. 116 (1): 17–22. doi:10.1002/ajmg.b.10041. PMID 12497607.
  • Coleman SK, Cai C, Mottershead DG, et al. (2003). "Surface expression of GluR-D AMPA receptor is dependent on an interaction between its C-terminal domain and a 4.1 protein". J. Neurosci. 23 (3): 798–806. PMID 12574408.
  • Pasternack A, Coleman SK, Féthière J, et al. (2003). "Characterization of the functional role of the N-glycans in the AMPA receptor ligand-binding domain". J. Neurochem. 84 (5): 1184–92. doi:10.1046/j.1471-4159.2003.01611.x. PMID 12603841.
  • Kawahara Y, Ito K, Sun H, et al. (2004). "GluR4c, an alternative splicing isoform of GluR4, is abundantly expressed in the adult human brain". Brain Res. Mol. Brain Res. 127 (1–2): 150–5. doi:10.1016/j.molbrainres.2004.05.020. PMID 15306133.
  • Li G, Sheng Z, Huang Z, Niu L (2005). "Kinetic mechanism of channel opening of the GluRDflip AMPA receptor". Biochemistry. 44 (15): 5835–41. doi:10.1021/bi047413n. PMID 15823042.
  • Nuriya M, Oh S, Huganir RL (2005). "Phosphorylation-dependent interactions of alpha-Actinin-1/IQGAP1 with the AMPA receptor subunit GluR4". J. Neurochem. 95 (2): 544–52. doi:10.1111/j.1471-4159.2005.03410.x. PMID 16190873.
  • Kimura K, Wakamatsu A, Suzuki Y, et al. (2006). "Diversification of transcriptional modulation: Large-scale identification and characterization of putative alternative promoters of human genes". Genome Res. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.