GABRA3
Gamma-aminobutyric acid receptor subunit alpha-3is aproteinthat in humans is encoded by theGABRA3gene.[5]
Function[edit]
GABAis the major inhibitory neurotransmitter in the mammalian brain where it acts atGABAAreceptors,which are ligand-gatedchloride channels.Chloride conductance of these channels can be modulated by agents such asbenzodiazepinesthat bind to the GABAAreceptor. At least 16 distinct subunits of GABA-A receptors have been identified.[5]GABA receptors are composed of 5 subunits with an extracellular ligand binding domains and ion channel domains that are integral to the membrane. Ligand binding to these receptors activates the channel.[6]
Subunit selective ligands[edit]
Recent research has produced several ligands that are selective for GABAAreceptors containing the α3subunit. Subtype-selective agonists for α3produceanxiolyticeffects withoutsedative,amnesia,orataxia.[7]selective a3agonists also show lack ofdependence,[8]and could make them superior to currently marketed drugs.
Agonists[edit]
- Adipiplon
- PWZ-029(partial agonist at α3,partial inverse agonist at α5)
- TP003(Selective full agonist at α3)
Inverse agonists[edit]
RNA editing[edit]
| Editing element of GABA-3 exon 9 | |
|---|---|
 Conservedsecondary structureandsequence conservationof GABA3 | |
| Identifiers | |
| Symbol | GABA3 |
| Rfam | RF01803 |
| Other data | |
| RNAtype | Cis-reg; |
| Domain(s) | Eukaryota; |
| SO | SO:0005836 |
| PDBstructures | PDBe |
The GABRA3 transcript undergoespre-mRNAediting by theADARfamily of enzymes.[9]A-to-I editingchanges anisoleucinecodon to code for amethionineresidue. This editing is thought to be important forbrain development,as the level of editing is low at birth and becomes almost 100% in an adult brain.[9]
The editing occurs in an RNAstem-loopfound inexon9.[9]The structured loci was identified using a specialisedbioinformaticsscreen[10]of the human genome. The proposed function of the edit is to alterchloridepermeability of theGABA receptor.[9]
At the time of discovery,Kv1.1mRNA was the only previously knownmammaliancoding site containing both the edit sequence and the editing complementary sequence.[11]
Type[edit]
A to I RNA editing is catalyzed by a family ofadenosine deaminasesacting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them toinosine.Inosines are recognised asguanosineby the cells translational machinery. There are three members of the ADAR family ADARs 1–3, withADAR1andADAR2being the only enzymatically active members.ADAR3is thought to have a regulatory role in the brain. ADAR1 and ADAR 2 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 editing site was previously believed to be a single nucleotide polymorphism.[12]The editing site is found at amino acid 5 of transmembrane domain 3 of exon 9. The predicted double-stranded RNA structure is interrupted by three bulges and a mismatch at the editing site. The double-stranded region is 22 base pairs in length. As with editing of the KCNA1 gene product,[11]the editing region and the editing complementary sequence are both found in exonic regions. In the pre=mRNA of GABRA3, both are found within exon 9.[9]The other subunits of the receptor are thought not to be edited, as their predicted secondary structure is less likely to be edited. Also, alpha subunits 1 and 6 have a uridine instead of an adenosine at the site corresponding to the editing site in alpha subunit 3.[9]Point mutation experiments determined that a Cytidine 15 nucleotides from the editing site is the base opposite the edited base.[9]Using a GABRA3 mini-gene that encodes for exon 9 cotransfected to HEK293 cells with either ADAR1 or -2 or none, it was determined that both active ADARs can efficiently edited the site in exon 9.[9]
Regulation[edit]
The mRNA expression of the alpha 3 subunit is developmentally regulated. It is the dominant subunit in the forebrain tissue at birth, gradually decreasing in prominence as alpha subunit 1 takes over. Also experiments with mice have demonstrated that editing of pre-mRNA alpha 3 subunit increases from 50% at birth to nearly 100% in adult.[9]Editing levels are lower in the hippocampus[13]
Conservation[edit]
At the location corresponding to the I/M site of GABRA3 in frog and pufferfish there is a genomically encoded methionine. In all other species, there is an isoleucine at the position.[14]
Consequences[edit]
Structure[edit]
Editing results in a codon change from (AUA) I to (AUG) M at the editing site. This results in translation of a methionine instead of an isoleucine at the I/M site. The amino acid change occurs in the transmembrane domain 3. The 4 transmembrane domains of each of the 5 subunits that make up the receptor interact to form the receptor channel. It is likely that the change of amino acids disturbs the structure, effecting gating and inactivation of the channel.[15]This is because methionine has a larger side chain.[9]
Function[edit]
While the effect of editing on protein function is unknown, the developmental increase in editing does correspond to changes in function of the GABAAreceptor. GABA binding leads to chloride channel activation, resulting in rapid increase in concentration of the ion. Initially, the receptor is an excitatory receptor, mediating depolarisation (efflux of Cl−ions) in immature neurons before changing to an inhibitory receptor, mediating hyperpolarisation (influx of Cl−ions) later on.[16]GABAAconverts to an inhibitory receptor from an excitatory receptor by the upregulation ofKCC2cotransporter. This decreases the concentration of Cl−ion within cells. Therefore, the GAGAAsubunits are involved in determining the nature of the receptor in response to GABA ligand.[17]These changes suggest that editing of the subunit is important in the developing brain by regulating the Cl−permeability of the channel during development. The unedited receptor is activated faster and deactivates slower than the edited receptor.[9]
See also[edit]
References[edit]
- ^abcGRCh38: Ensembl release 89: ENSG00000011677–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000031343–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.
- ^ab"Entrez Gene: GABRA3 gamma-aminobutyric acid (GABA) A receptor, alpha 3".
- ^Cromer BA, Morton CJ, Parker MW (June 2002). "Anxiety over GABA(A) receptor structure relieved by AChBP".Trends in Biochemical Sciences.27(6): 280–287.doi:10.1016/S0968-0004(02)02092-3.PMID12069787.
- ^Fischer BD, Atack JR, Platt DM, et al. (2011)."Contribution of GABAA receptors containing α3 subunits to the therapeutic-related and side effects of benzodiazepine-type drugs in monkeys".Psychopharmacology.215(2): 311–319.doi:10.1007/s00213-010-2142-y.PMC3097109.PMID21190016.
- ^Cheng T, Wallace D, Ponteri B, et al. (2018)."Valium without dependence? Individual GABAA receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects".Neuropsychiatr. Dis. Treat.14:1351–1361.doi:10.2147/NDT.S164307.PMC5973310.PMID29872302.
- ^abcdefghijkOhlson J, Pedersen JS, Haussler D, Ohman M (May 2007)."Editing modifies the GABA(A) receptor subunit alpha3".RNA.13(5): 698–703.doi:10.1261/rna.349107.PMC1852825.PMID17369310.
- ^Ohlson J, Ensterö M, Sjöberg BM, Ohman M (October 2005)."A method to find tissue-specific novel sites of selective adenosine deamination".Nucleic Acids Research.33(19): e167.doi:10.1093/nar/gni169.PMC1275595.PMID16257978.
- ^abBhalla T, Rosenthal JJ, Holmgren M, Reenan R (October 2004). "Control of human potassium channel inactivation by editing of a small mRNA hairpin".Nature Structural & Molecular Biology.11(10): 950–956.doi:10.1038/nsmb825.PMID15361858.S2CID34081059.
- ^Wang Q, Miyakoda M, Yang W, Khillan J, Stachura DL, Weiss MJ, Nishikura K (February 2004)."Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene".The Journal of Biological Chemistry.279(6): 4952–4961.doi:10.1074/jbc.M310162200.PMID14613934.
- ^Rula EY, Lagrange AH, Jacobs MM, Hu N, Macdonald RL, Emeson RB (June 2008)."Developmental modulation of GABA(A) receptor function by RNA editing".The Journal of Neuroscience.28(24): 6196–6201.doi:10.1523/JNEUROSCI.0443-08.2008.PMC2746000.PMID18550761.
- ^Hinrichs AS, Karolchik D, Baertsch R, Barber GP, Bejerano G, Clawson H, Diekhans M, Furey TS, Harte RA, Hsu F, Hillman-Jackson J, Kuhn RM, Pedersen JS, Pohl A, Raney BJ, Rosenbloom KR, Siepel A, Smith KE, Sugnet CW, Sultan-Qurraie A, Thomas DJ, Trumbower H, Weber RJ, Weirauch M, Zweig AS, Haussler D, Kent WJ (January 2006)."The UCSC Genome Browser Database: update 2006".Nucleic Acids Research.34(Database issue): D590–8.doi:10.1093/nar/gkj144.PMC1347506.PMID16381938.
- ^Fisher JL (April 2004). "A mutation in the GABAA receptor alpha 1 subunit linked to human epilepsy affects channel gating properties".Neuropharmacology.46(5): 629–637.doi:10.1016/j.neuropharm.2003.11.015.PMID14996540.S2CID35096410.
- ^Ben-Ari Y (September 2002). "Excitatory actions of gaba during development: the nature of the nurture".Nature Reviews. Neuroscience.3(9): 728–739.doi:10.1038/nrn920.PMID12209121.S2CID8116740.
- ^Böhme I, Rabe H, Lüddens H (August 2004)."Four amino acids in the alpha subunits determine the gamma-aminobutyric acid sensitivities of GABAA receptor subtypes".The Journal of Biological Chemistry.279(34): 35193–35200.doi:10.1074/jbc.M405653200.PMID15199051.
Further reading[edit]
- Buckle VJ, Fujita N, Ryder-Cook AS, Derry JM, Barnard PJ, Lebo RV, Schofield PR, Seeburg PH, Bateson AN, Darlison MG (November 1989). "Chromosomal localization of GABAA receptor subunit genes: relationship to human genetic disease".Neuron.3(5): 647–654.doi:10.1016/0896-6273(89)90275-4.PMID2561974.S2CID8532075.
- Bell MV, Bloomfield J, McKinley M, Patterson MN, Darlison MG, Barnard EA, Davies KE (December 1989)."Physical linkage of a GABAA receptor subunit gene to the DXS374 locus in human Xq28".American Journal of Human Genetics.45(6): 883–888.PMC1683479.PMID2574000.
- Tögel M, Mossier B, Fuchs K, Sieghart W (April 1994)."gamma-Aminobutyric acidA receptors displaying association of gamma 3-subunits with beta 2/3 and different alpha-subunits exhibit unique pharmacological properties".The Journal of Biological Chemistry.269(17): 12993–12998.doi:10.1016/S0021-9258(18)99974-6.PMID8175718.
- Hadingham KL, Wingrove P, Le Bourdelles B, Palmer KJ, Ragan CI, Whiting PJ (June 1993). "Cloning of cDNA sequences encoding human alpha 2 and alpha 3 gamma-aminobutyric acidA receptor subunits and characterization of the benzodiazepine pharmacology of recombinant alpha 1-, alpha 2-, alpha 3-, and alpha 5-containing human gamma-aminobutyric acidA receptors".Molecular Pharmacology.43(6): 970–975.PMID8391122.
- Belelli D, Lambert JJ, Peters JA, Wafford K, Whiting PJ (September 1997)."The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid".Proceedings of the National Academy of Sciences of the United States of America.94(20): 11031–11036.Bibcode:1997PNAS...9411031B.doi:10.1073/pnas.94.20.11031.PMC23576.PMID9380754.
- Huang RQ, Dillon GH (July 1998). "Maintenance of recombinant type A gamma-aminobutyric acid receptor function: role of protein tyrosine phosphorylation and calcineurin".The Journal of Pharmacology and Experimental Therapeutics.286(1): 243–255.PMID9655866.
- Amir R, Dahle EJ, Toriolo D, Zoghbi HY (January 2000). "Candidate gene analysis in Rett syndrome and the identification of 21 SNPs in Xq".American Journal of Medical Genetics.90(1): 69–71.doi:10.1002/(SICI)1096-8628(20000103)90:1<69::AID-AJMG12>3.0.CO;2-W.PMID10602120.
- Bedford FK, Kittler JT, Muller E, Thomas P, Uren JM, Merlo D, Wisden W, Triller A, Smart TG, Moss SJ (September 2001). "GABA(A) receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1".Nature Neuroscience.4(9): 908–916.doi:10.1038/nn0901-908.PMID11528422.S2CID13078743.
- Chou KC (April 2004). "Modelling extracellular domains of GABA-A receptors: subtypes 1, 2, 3, and 5".Biochemical and Biophysical Research Communications.316(3): 636–642.doi:10.1016/j.bbrc.2004.02.098.PMID15033447.
- Henkel V, Baghai TC, Eser D, Zill P, Mergl R, Zwanzger P, Schüle C, Bottlender R, Jäger M, Rupprecht R, Hegerl U, Möller HJ, Bondy B (April 2004). "The gamma amino butyric acid (GABA) receptor alpha-3 subunit gene polymorphism in unipolar depressive disorder: a genetic association study".American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics.126B(1): 82–87.doi:10.1002/ajmg.b.20137.PMID15048654.S2CID26012998.
- Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S (January 2006)."Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes".Genome Research.16(1): 55–65.doi:10.1101/gr.4039406.PMC1356129.PMID16344560.
- Pedersen JS, Bejerano G, Siepel A, Rosenbloom K, Lindblad-Toh K, Lander ES, Kent J, Miller W, Haussler D (April 2006)."Identification and classification of conserved RNA secondary structures in the human genome".PLOS Computational Biology.2(4): e33.Bibcode:2006PLSCB...2...33P.doi:10.1371/journal.pcbi.0020033.PMC1440920.PMID16628248.
External links[edit]
- GABRA3+protein,+humanat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
- [1]
- Page for Editing element of GABA-3 exon 9atRfam
This article incorporates text from theUnited States National Library of Medicine,which is in thepublic domain.