GRIA3

Glutamate receptor 3 is a protein that in humans is encoded by the GRIA3 gene.^[5][6][7]

GRIA3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3LSW, 3LSX
Identifiers
Aliases	GRIA3, GLUR-C, GLUR-K3, GLUR3, GLURC, GluA3, MRX94, glutamate ionotropic receptor AMPA type subunit 3, MRXSW
External IDs	OMIM: 305915; MGI: 95810; HomoloGene: 37353; GeneCards: GRIA3; OMA:GRIA3 - orthologs
Gene location (Human) Chr. X chromosome (human)[1] Band Xq25 Start 123,184,153 bp[1] End 123,490,915 bp[1]
Gene location (Mouse) Chr. X chromosome (mouse)[2] Band X A4|X 23.19 cM Start 40,489,731 bp[2] End 40,767,478 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Brodmann area 23 middle temporal gyrus primary visual cortex entorhinal cortex postcentral gyrus superior frontal gyrus Brodmann area 9 right frontal lobe prefrontal cortex hippocampus proper Top expressed in subiculum anterior amygdaloid area olfactory tubercle dorsal striatum lateral septal nucleus nucleus accumbens lateral geniculate nucleus facial motor nucleus lobe of cerebellum prefrontal cortex More reference expression data BioGPS More reference expression data
Gene ontology Molecular function ion channel activity ionotropic glutamate receptor activity extracellularly glutamate-gated ion channel activity AMPA glutamate receptor activity excitatory extracellular ligand-gated ion channel activity amyloid-beta binding signaling receptor activity transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential Cellular component integral component of membrane endocytic vesicle membrane postsynaptic membrane membrane synapse cell junction AMPA glutamate receptor complex plasma membrane parallel fiber to Purkinje cell synapse Biological process glutamate receptor signaling pathway ion transport ion transmembrane transport ionotropic glutamate receptor signaling pathway transport excitatory postsynaptic potential regulation of postsynaptic membrane potential regulation of NMDA receptor activity Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2892 53623 Ensembl ENSG00000125675 ENSMUSG00000001986 UniProt P42263 Q9Z2W9 RefSeq (mRNA) NM_181894 NM_000828 NM_001256743 NM_007325 NM_001281929 NM_016886 NM_001290451 NM_001358361 RefSeq (protein) NP_000819 NP_001243672 NP_015564 NP_001268858 NP_001277380 NP_058582 NP_001345290 Location (UCSC) Chr X: 123.18 – 123.49 Mb Chr X: 40.49 – 40.77 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Function

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.^[7]

Genome studies have uncovered a tentative link between defective GRIA3 variants and a highly elevated risk of schizophrenia.

Interactions

GRIA3 has been shown to interact with GRIP1^[8] and PICK1.^[8]

RNA editing

Several ion channels and neurotransmitters receptors pre-mRNA as substrates for ADARs.^[9] This includes 5 subunits of the glutamate receptor: ionotropic AMPA glutamate receptor subunits (GluA2, GluA3, GluA4) and kainate receptor subunits (GluK1, GluK2). 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 K_v1.1 channel).^[10] The human K_v1.1 channel pre mRNA is also subject to A to I RNA editing.^[11] 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

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

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.^[12] The editing complementary 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 at 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.^[12][13]

Conservation

Editing also occurs in rat.^[12]

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.^[12] 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.^[14]

Consequences

Structure

Editing results in a codon change from (AGA) to (GGA), an R to a G change at the editing site.^[12]

Function

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.^[12] Editing is also thought to affect splicing at this site.

See also

• AMPA receptor

References

1. GRCh38: Ensembl release 89: ENSG00000125675 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000001986 – 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. 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. doi:10.1523/JNEUROSCI.12-07-02555.1992. PMC 6575855. PMID 1319477.
6. 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.
7. "Entrez Gene: GRIA3 glutamate receptor, ionotrophic, AMPA 3".
8. 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. hdl:2262/89271. ISSN 0021-9258. PMID 11891216.
9. 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.
10. 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. S2CID 11969068.
11. 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. S2CID 34081059.
12. 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. Bibcode:1994Sci...266.1709L. doi:10.1126/science.7992055. PMID 7992055.
13. 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. S2CID 12147763.
14. 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

• Hollmann M, Hartley M, Heinemann S (1991). "Ca2+ permeability of KA-AMPA--gated glutamate receptor channels depends on subunit composition". Science. 252 (5007): 851–3. Bibcode:1991Sci...252..851H. doi:10.1126/science.1709304. PMID 1709304. S2CID 27103108.
• Rampersad V, Elliott CE, Nutt SL, et al. (1994). "Human glutamate receptor hGluR3 flip and flop isoforms: cloning and sequencing of the cDNAs and primary structure of the proteins". Biochim. Biophys. Acta. 1219 (2): 563–6. doi:10.1016/0167-4781(94)90090-6. PMID 7918660.
• Rogers SW, Andrews PI, Gahring LC, et al. (1994). "Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis". Science. 265 (5172): 648–51. Bibcode:1994Sci...265..648R. doi:10.1126/science.8036512. PMID 8036512.
• Tomiyama M, Rodriguez-Puertas R, Cortés R, et al. (1997). "Differential regional distribution of AMPA receptor subunit messenger RNAs in the human spinal cord as visualized by in situ hybridization". Neuroscience. 75 (3): 901–15. doi:10.1016/0306-4522(96)00321-1. hdl:10261/112658. PMID 8951883. S2CID 20271430.
• Osten P, Srivastava S, Inman GJ, et al. (1998). "The AMPA receptor GluR2 C terminus can mediate a reversible, ATP-dependent interaction with NSF and alpha- and beta-SNAPs". Neuron. 21 (1): 99–110. doi:10.1016/S0896-6273(00)80518-8. PMID 9697855.
• Srivastava S, Osten P, Vilim FS, et al. (1998). "Novel anchorage of GluR2/3 to the postsynaptic density by the AMPA receptor-binding protein ABP". Neuron. 21 (3): 581–91. doi:10.1016/S0896-6273(00)80568-1. PMID 9768844.
• Hayashi T, Umemori H, Mishina M, Yamamoto T (1999). "The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn". Nature. 397 (6714): 72–6. Bibcode:1999Natur.397...72H. doi:10.1038/16269. PMID 9892356. S2CID 4327273.
• Amir R, Dahle EJ, Toriolo D, Zoghbi HY (2000). "Candidate gene analysis in Rett syndrome and the identification of 21 SNPs in Xq". Am. J. Med. Genet. 90 (1): 69–71. doi:10.1002/(SICI)1096-8628(20000103)90:1<69::AID-AJMG12>3.0.CO;2-W. PMID 10602120.
• Aruscavage PJ, Bass BL (2000). "A phylogenetic analysis reveals an unusual sequence conservation within introns involved in RNA editing". RNA. 6 (2): 257–69. doi:10.1017/S1355838200991921. PMC 1369911. PMID 10688364.
• Gahring L, Carlson NG, Meyer EL, Rogers SW (2001). "Granzyme B proteolysis of a neuronal glutamate receptor generates an autoantigen and is modulated by glycosylation". J. Immunol. 166 (3): 1433–8. doi:10.4049/jimmunol.166.3.1433. PMID 11160179.
• Liu QJ, Gong YQ, Chen BX, et al. (2001). "[Linkage analysis and mutation detection of GRIA3 in Smith--Fineman--Myers syndrome]". Yi Chuan Xue Bao. 28 (11): 985–90. PMID 11725645.
• 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. hdl:2262/89271. PMID 11891216.
• Wyszynski M, Kim E, Dunah AW, et al. (2002). "Interaction between GRIP and liprin-alpha/SYD2 is required for AMPA receptor targeting". Neuron. 34 (1): 39–52. doi:10.1016/S0896-6273(02)00640-2. PMID 11931740.
• 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. CiteSeerX 10.1.1.575.9300. doi:10.1002/syn.10098. PMID 12125045. S2CID 28604714.
• 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.
• Ganor Y, Besser M, Ben-Zakay N, et al. (2003). "Human T cells express a functional ionotropic glutamate receptor GluR3, and glutamate by itself triggers integrin-mediated adhesion to laminin and fibronectin and chemotactic migration". J. Immunol. 170 (8): 4362–72. doi:10.4049/jimmunol.170.8.4362. PMID 12682273.
• Flajolet M, Rakhilin S, Wang H, et al. (2004). "Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3". Proc. Natl. Acad. Sci. U.S.A. 100 (26): 16006–11. Bibcode:2003PNAS..10016006F. doi:10.1073/pnas.2136600100. PMC 307683. PMID 14663150.
• Kolleker A, Zhu JJ, Schupp BJ, et al. (2004). "Glutamatergic plasticity by synaptic delivery of GluR-B(long)-containing AMPA receptors". Neuron. 40 (6): 1199–212. doi:10.1016/S0896-6273(03)00722-0. PMID 14687553.

External links

• GRIA3+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• "DARNED".
• http://darned.ucc.ie
• Overview of all the structural information available in the PDB for UniProt: Q9Z2W9 (Glutamate receptor 3) at the PDBe-KB.

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