GRIA3
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Glutamate receptor 3 is a protein that in humans is encoded by the GRIA3 gene.[5][6][7]
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
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 Kv1.1 channel).[10] The human Kv1.1 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
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
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000125675 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000001986 – 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.
- PMID 1319477.
- PMID 10644433.
- ^ a b "Entrez Gene: GRIA3 glutamate receptor, ionotrophic, AMPA 3".
- ^ PMID 11891216.
- PMID 12045112.
- S2CID 11969068.
- S2CID 34081059.
- ^ PMID 7992055.
- S2CID 12147763.
- 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.