GRIA4
| GRIA4 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | GRIA4, GLUR4, GLUR4C, GLURD, GluA4, glutamate ionotropic receptor AMPA type subunit 4, NEDSGA, GluA4-ATD | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 138246; MGI: 95811; HomoloGene: 20227; GeneCards: GRIA4; OMA:GRIA4 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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] Like the other AMPA receptor subunits, GluA4 occurs as flip and flop spliced variant.[6] In addition, GluA4 CTD long and short isoforms exist, and presumably an ATD-only isoform (433 aa).[7]
Interactions
GRIA4 has been shown to interact with CACNG2,[8] GRIP1,[9] PICK1[9] and PRKCG.[10]
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.
Type
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).
Location
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.[6] 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.[6][11]
Conservation
Editing also occurs in rat.[6]
Regulation
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.[6] 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.[12]
Consequences
Structure
Editing results in a codon change from (AGA) to (GGA), an R to a G change at the editing site.[6]
Function
AMPA receptors that occur in the flop form desensitise faster than the flip form. 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.
Splicing
A crosstalk between editing and splicing may occur here. Editing takes place before splicing. Like the other AMPA receptor subunits, GluA4 occurs as flip and flop spliced variant.[6] Editing is also thought to affect splicing at this site.
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000152578 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025892 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "Entrez Gene: GRIA4 glutamate receptor, ionotrophic, AMPA 4".
- ^ a b c d e f g Lomeli H, Mosbacher J, Melcher T, Höger T, Geiger JR, Kuner T, Monyer H, Higuchi M, Bach A, Seeburg PH (December 1994). "Control of kinetic properties of AMPA receptor channels by nuclear RNA editing". Science. 266 (5191): 1709–1713. Bibcode:1994Sci...266.1709L. doi:10.1126/science.7992055. PMID 7992055.
- ^ Herbrechter R, Hube N, Buchholz R, Reiner A (July 2021). "Splicing and editing of ionotropic glutamate receptors: a comprehensive analysis based on human RNA-Seq data". Cellular and Molecular Life Sciences. 78 (14): 5605–5630. doi:10.1007/s00018-021-03865-z. ISSN 1420-682X. PMC 8257547. PMID 34100982.
- ^ Chen L, Chetkovich DM, Petralia RS, Sweeney NT, Kawasaki Y, Wenthold RJ, Bredt DS, Nicoll RA (2000). "Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms". Nature. 408 (6815): 936–943. Bibcode:2000Natur.408..936C. doi:10.1038/35050030. PMID 11140673. S2CID 4427689.
- ^ a b Hirbec H, Perestenko O, Nishimune A, Meyer G, Nakanishi S, Henley JM, Dev KK (May 2002). "The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs". The Journal of Biological Chemistry. 277 (18): 15221–15224. doi:10.1074/jbc.C200112200. hdl:2262/89271. PMID 11891216.
- ^ Correia SS, Duarte CB, Faro CJ, Pires EV, Carvalho AL (February 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". The Journal of Biological Chemistry. 278 (8): 6307–6313. doi:10.1074/jbc.M205587200. hdl:10316/12633. PMID 12471040.
- ^ Seeburg PH, Higuchi M, Sprengel R (May 1998). "RNA editing of brain glutamate receptor channels: mechanism and physiology". Brain Research. Brain Research Reviews. 26 (2–3): 217–229. doi:10.1016/S0165-0173(97)00062-3. PMID 9651532. S2CID 12147763.
- ^ 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". Proceedings of the National Academy of Sciences of the United States of America. 93 (5): 1875–1880. Bibcode:1996PNAS...93.1875H. doi:10.1073/pnas.93.5.1875. PMC 39875. PMID 8700852.
Further reading
- McNamara JO, Eubanks JH, McPherson JD, Wasmuth JJ, Evans GA, Heinemann SF (July 1992). "Chromosomal localization of human glutamate receptor genes". The Journal of Neuroscience. 12 (7): 2555–2562. doi:10.1523/JNEUROSCI.12-07-02555.1992. PMC 6575855. PMID 1319477.
- Hardy M, Younkin D, Tang CM, Pleasure J, Shi QY, Williams M, Pleasure D (August 1994). "Expression of non-NMDA glutamate receptor channel genes by clonal human neurons". Journal of Neurochemistry. 63 (2): 482–489. doi:10.1046/j.1471-4159.1994.63020482.x. PMID 7518497. S2CID 19882589.
- Roche KW, Raymond LA, Blackstone C, Huganir RL (April 1994). "Transmembrane topology of the glutamate receptor subunit GluR6". The Journal of Biological Chemistry. 269 (16): 11679–11682. doi:10.1016/S0021-9258(17)32623-6. PMID 8163463.
- Fletcher EJ, Nutt SL, Hoo KH, Elliott CE, Korczak B, McWhinnie EA, Kamboj RK (1996). "Cloning, expression and pharmacological characterization of a human glutamate receptor: hGluR4". Receptors & Channels. 3 (1): 21–31. PMID 8589990.
- Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
- Ripellino JA, Neve RL, Howe JR (January 1998). "Expression and heteromeric interactions of non-N-methyl-D-aspartate glutamate receptor subunits in the developing and adult cerebellum". Neuroscience. 82 (2): 485–497. doi:10.1016/S0306-4522(97)00296-0. PMID 9466455. S2CID 23219004.
- Carvalho AL, Kameyama K, Huganir RL (June 1999). "Characterization of phosphorylation sites on the glutamate receptor 4 subunit of the AMPA receptors". The Journal of Neuroscience. 19 (12): 4748–4754. doi:10.1523/JNEUROSCI.19-12-04748.1999. PMC 6782640. PMID 10366608.
- Chen L, Chetkovich DM, Petralia RS, Sweeney NT, Kawasaki Y, Wenthold RJ, Bredt DS, Nicoll RA (2001). "Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms". Nature. 408 (6815): 936–943. Bibcode:2000Natur.408..936C. doi:10.1038/35050030. PMID 11140673. S2CID 4427689.
- Hirbec H, Perestenko O, Nishimune A, Meyer G, Nakanishi S, Henley JM, Dev KK (May 2002). "The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs". The Journal of Biological Chemistry. 277 (18): 15221–15224. doi:10.1074/jbc.C200112200. hdl:2262/89271. PMID 11891216.
- Tomiyama M, Rodríguez-Puertas R, Cortés R, Pazos A, Palacios JM, Mengod G (September 2002). "Flip and flop splice variants of AMPA receptor subunits in the spinal cord of amyotrophic lateral sclerosis". Synapse. 45 (4): 245–249. CiteSeerX 10.1.1.575.9300. doi:10.1002/syn.10098. PMID 12125045. S2CID 28604714.
- Pasternack A, Coleman SK, Jouppila A, Mottershead DG, Lindfors M, Pasternack M, Keinänen K (December 2002). "Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor channels lacking the N-terminal domain". The Journal of Biological Chemistry. 277 (51): 49662–49667. doi:10.1074/jbc.M208349200. PMID 12393905.
- Correia SS, Duarte CB, Faro CJ, Pires EV, Carvalho AL (February 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". The Journal of Biological Chemistry. 278 (8): 6307–6313. doi:10.1074/jbc.M205587200. hdl:10316/12633. PMID 12471040.
- Makino C, Fujii Y, Kikuta R, Hirata N, Tani A, Shibata A, Ninomiya H, Tashiro N, Shibata H, Fukumaki Y (January 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". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 116B (1): 17–22. doi:10.1002/ajmg.b.10041. PMID 12497607. S2CID 24883590.
- Coleman SK, Cai C, Mottershead DG, Haapalahti JP, Keinänen K (February 2003). "Surface expression of GluR-D AMPA receptor is dependent on an interaction between its C-terminal domain and a 4.1 protein". The Journal of Neuroscience. 23 (3): 798–806. doi:10.1523/JNEUROSCI.23-03-00798.2003. PMC 6741938. PMID 12574408.
- Pasternack A, Coleman SK, Féthière J, Madden DR, LeCaer JP, Rossier J, Pasternack M, Keinänen K (March 2003). "Characterization of the functional role of the N-glycans in the AMPA receptor ligand-binding domain". Journal of Neurochemistry. 84 (5): 1184–1192. doi:10.1046/j.1471-4159.2003.01611.x. PMID 12603841. S2CID 11350496.
- Kawahara Y, Ito K, Sun H, Ito M, Kanazawa I, Kwak S (August 2004). "GluR4c, an alternative splicing isoform of GluR4, is abundantly expressed in the adult human brain". Brain Research. Molecular Brain Research. 127 (1–2): 150–155. doi:10.1016/j.molbrainres.2004.05.020. PMID 15306133.
- Li G, Sheng Z, Huang Z, Niu L (April 2005). "Kinetic mechanism of channel opening of the GluRDflip AMPA receptor". Biochemistry. 44 (15): 5835–5841. doi:10.1021/bi047413n. PMID 15823042.
- Nuriya M, Oh S, Huganir RL (October 2005). "Phosphorylation-dependent interactions of alpha-Actinin-1/IQGAP1 with the AMPA receptor subunit GluR4". Journal of Neurochemistry. 95 (2): 544–552. doi:10.1111/j.1471-4159.2005.03410.x. PMID 16190873. S2CID 9517535.
External links
- GRIA4+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.