GRIA3

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Glutamate receptor, ionotropic, AMPA 3
Identifiers
Symbols GRIA3 ; GLUR-C; GLUR-K3; GLUR3; GLURC; GluA3; MRX94
External IDs OMIM305915 MGI95810 HomoloGene37353 IUPHAR: GluA3 ChEMBL: 3595 GeneCards: GRIA3 Gene
RNA expression pattern
PBB GE GRIA3 206730 at tn.png
PBB GE GRIA3 208032 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2892 53623
Ensembl ENSG00000125675 ENSMUSG00000001986
UniProt P42263 Q9Z2W9
RefSeq (mRNA) NM_000828 NM_016886
RefSeq (protein) NP_000819 NP_058582
Location (UCSC) Chr X:
122.32 – 122.62 Mb
Chr X:
41.4 – 41.68 Mb
PubMed search [1] [2]

Glutamate receptor 3 is a protein that in humans is encoded by the GRIA3 gene.[1][2][3]

Function[edit]

Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. This gene belongs to a family of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. Alternative splicing at this locus results in several different isoforms which may vary in their signal transduction properties.[3]

Interactions[edit]

GRIA3 has been shown to interact with GRIP1[4] and PICK1.[4]

RNA editing[edit]

Several ion channels and neurotransmitters receptors pre-mRNA as substrates for ADARs.[5] 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 with each subunit contributing to the pore loop structure. The pore loop structure is related to that found in K+ channels (e.g., human Kv1.1 channel).[6] The human Kv1.1 channel pre mRNA is also subject to A to I RNA editing.[7] The function of the glutamate receptors 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 necessarily high diversity of these receptors. GluR3 is a gene product of the GRIA3 gene and its pre-mRNA is subject to RNA editing.

Type[edit]

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 ADAR1 and ADAR2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues while ADAR3 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[edit]

The pre-mRNA of this subunit is edited at one position. The R/G editing site is located in exon 13 between the M3 and M4 regions. 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. The R/G site is found at amino acid 769 immediately before the 38-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.[8] The editing complimentary sequence (ECS) is found in an intronic sequence close to the exon. The intronic sequence includes a 5' splice site. 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 a 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.[8][9]

Conservation[edit]

Editing also occurs in rat.[8]

Regulation[edit]

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.[8] 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.[10]

Consequences[edit]

Structure[edit]

Editing results in a codon change from (AGA) to (GGA), an R to a G change at the editing site.[8]

Function[edit]

Editing at R/G site allows for faster recovery from desensitisation. Unedited Glu-R at this site have slower recovery rates. Editing, therefore, allow 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.[8] Editing is also thought to affect splicing at this site.

See also[edit]

References[edit]

  1. ^ McNamara JO, Eubanks JH, McPherson JD, Wasmuth JJ, Evans GA, Heinemann SF (Jul 1992). "Chromosomal localization of human glutamate receptor genes". J Neurosci 12 (7): 2555–62. PMID 1319477. 
  2. ^ Gecz J, Barnett S, Liu J, Hollway G, Donnelly A, Eyre H, Eshkevari HS, Baltazar R, Grunn A, Nagaraja R, Gilliam C, Peltonen L, Sutherland GR, Baron M, Mulley JC (Mar 2000). "Characterization of the human glutamate receptor subunit 3 gene (GRIA3), a candidate for bipolar disorder and nonspecific X-linked mental retardation". Genomics 62 (3): 356–68. doi:10.1006/geno.1999.6032. PMID 10644433. 
  3. ^ a b "Entrez Gene: GRIA3 glutamate receptor, ionotrophic, AMPA 3". 
  4. ^ 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. (United States) 277 (18): 15221–4. doi:10.1074/jbc.C200112200. ISSN 0021-9258. PMID 11891216. 
  5. ^ Bass BL (2002). "RNA editing by adenosine deaminases that act on RNA". Annu. Rev. Biochem. 71: 817–46. doi:10.1146/annurev.biochem.71.110601.135501. PMC 1823043. PMID 12045112. 
  6. ^ Seeburg PH, Single F, Kuner T, Higuchi M, Sprengel R (July 2001). "Genetic manipulation of key determinants of ion flow in glutamate receptor channels in the mouse". Brain Res. 907 (1-2): 233–43. doi:10.1016/S0006-8993(01)02445-3. PMID 11430906. 
  7. ^ Bhalla T, Rosenthal JJ, Holmgren M, Reenan R (October 2004). "Control of human potassium channel inactivation by editing of a small mRNA hairpin". Nat. Struct. Mol. Biol. 11 (10): 950–6. doi:10.1038/nsmb825. PMID 15361858. 
  8. ^ a b c d e f 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): 1709–13. doi:10.1126/science.7992055. PMID 7992055. 
  9. ^ 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. 
  10. ^ 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. doi:10.1073/pnas.93.5.1875. PMC 39875. PMID 8700852. 

External sources[edit]

Further reading[edit]

External links[edit]

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