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AliasesGRIA4, GLUR4, GLUR4C, GLURD, GluA4, glutamate ionotropic receptor AMPA type subunit 4, NEDSGA
External IDsOMIM: 138246 MGI: 95811 HomoloGene: 20227 GeneCards: GRIA4
Gene location (Human)
Chromosome 11 (human)
Chr.Chromosome 11 (human)[1]
Chromosome 11 (human)
Genomic location for GRIA4
Genomic location for GRIA4
Band11q22.3Start105,609,994 bp[1]
End105,982,092 bp[1]
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 11: 105.61 – 105.98 MbChr 9: 4.42 – 4.8 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Glutamate receptor 4 is a protein that in humans is encoded by the GRIA4 gene.[5]

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.[5]


GRIA4 has been shown to interact with CACNG2,[6] GRIP1,[7] PICK1[7] and PRKCG.[8]

RNA editing[edit]

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.[9] The editing complementary 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.[9][10]


Editing also occurs in rat.[9]


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.[9] 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.[11]



Editing results in a codon change from (AGA) to (GGA), an R to a G change at the editing site.[9]


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.[9] Editing is also thought to affect splicing at this site

See also[edit]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000152578 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025892 - 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. ^ a b "Entrez Gene: GRIA4 glutamate receptor, ionotrophic, AMPA 4".
  6. ^ 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. 408 (6815): 936–43. doi:10.1038/35050030. ISSN 0028-0836. PMID 11140673.
  7. ^ a b 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. 277 (18): 15221–4. doi:10.1074/jbc.C200112200. ISSN 0021-9258. PMID 11891216.
  8. ^ 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. 278 (8): 6307–13. doi:10.1074/jbc.M205587200. ISSN 0021-9258. PMID 12471040.
  9. ^ a b c d e f 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.
  10. ^ 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.
  11. ^ 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[edit]

External links[edit]

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