GABRA2

GABRA2
Identifiers
Aliases	GABRA2, gamma-aminobutyric acid type A receptor alpha2 subunit
External IDs	OMIM: 137140; MGI: 95614; HomoloGene: 20217; GeneCards: GABRA2; OMA:GABRA2 - orthologs
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4p12 Start 46,248,427 bp[1] End 46,475,230 bp[1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in frontal pole entorhinal cortex postcentral gyrus Brodmann area 23 superior frontal gyrus middle temporal gyrus Occipital Lobe primary visual cortex Brodmann area 46 caudate nucleus n/a More reference expression data BioGPS More reference expression data
Gene ontology Molecular function GABA-A receptor activity ion channel activity benzodiazepine receptor activity extracellular ligand-gated ion channel activity chloride channel activity GABA-gated chloride ion channel activity transmembrane signaling receptor activity inhibitory extracellular ligand-gated ion channel activity transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential Cellular component integral component of membrane chloride channel complex membrane synapse plasma membrane cell junction integral component of synaptic vesicle membrane postsynaptic membrane cytoplasmic vesicle membrane cytoplasmic vesicle GABA-A receptor complex integral component of plasma membrane dendrite membrane neuron projection postsynapse dendrite cell projection Biological process gamma-aminobutyric acid signaling pathway chloride transport regulation of neurotransmitter levels neurotransmitter transport ion transport chloride transmembrane transport ion transmembrane transport signal transduction chemical synaptic transmission regulation of membrane potential nervous system process synaptic transmission, GABAergic regulation of postsynaptic membrane potential inhibitory synapse assembly Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2555 14395 Ensembl ENSG00000151834 n/a UniProt P47869 P26048 RefSeq (mRNA) NM_000807 NM_001114175 NM_001286827 NM_001330690 NM_008066 RefSeq (protein) NP_000798 NP_001107647 NP_001273756 NP_001317619 NP_001364073 NP_001364074 NP_001364075 NP_001364076 NP_001364077 NP_001364078 NP_001364079 NP_001364080 NP_001364081 NP_001364082 NP_001364083 NP_001364084 NP_032092 Location (UCSC) Chr 4: 46.25 – 46.48 Mb n/a PubMed search [2] [3]
Wikidata
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GABA receptor types and their clinical functions. Notice that α2 receptor type refers to the GABRA2, an anxiolyte.

GABAA receptor animation demonstrates the various subunit types that make up the GABA receptor. All the variants of GABA (A) receptors have different functions within the mammalian brain.

Gamma-aminobutyric acid receptor subunit alpha-2 is a protein in humans that is encoded by the GABRA2 gene.^[4]

GABRA2 is an alpha subunit that is part of GABA-A receptors, which are ligand-gated chloride channels and are activated by the major inhibitory neurotransmitter in the mammalian brain, GABA. Chloride conductance of these channels can be modulated by agents, such as benzodiazepines (psychoactive drugs) that bind to the GABA-A receptor.

GABA-A receptors are composed of two alpha, two beta, and one gamma subunits. They have at least 16 distinct subunits identified, including GABRA2.^[5] This receptor is found mainly in specific regions of the brain, such as the hippocampus.^[6]

Subunit isoforms are seen around in various locations in the brain throughout growth. The combination of subunits has a large effect on the pharmacological and biophysical characteristics.^[7] GABRA2 has been found to mediate anxiolytic activity, which plays a key role in emotional and behavioral control. Most GABRA2 modifications have been found to be linked to alcoholism and adolescent behavior.

Structure

Shows the five subunits that comprise the GABA-A receptor. GABRA2 is only one alpha subunit in the structure demonstrated with the color red.

GABRA2 is one of the 16 distinct alpha subunits found for the GABA receptor. GABA-A has a pentametric form, with two alpha, two beta, and one gamma subunit.^[6] The various subunit isoforms seen in the GABA-A receptor structure have an effect on its function. GABRA2 is most often seen as part of the most common expression α2β3γ2, which is seen in 13% of all GABA-A receptors.^[7] The subunit, GABRA2, is found primarily in the hippocampus and/or the forebrain. It is more confined to areas of the brain in comparison to other alpha subunits seen in GABA-A receptors. It is present in 35% of all GABA-A receptors being the fourth most abundant subunit next to GABRA1 and various beta subunits. Like all subunits, it is made from structurally distinct proteins. The presence of this subunit causes an easier binding of benzodiazepine which is a category of psychoactive drugs.^[6]

Function

GABRA2 mediates neural activity necessary for information processing in inter-neurons.^[6] GABRA2 participates in transporting Cl⁻ ions into the membrane, since it forms part of the GABA-A receptor. The influx of Cl⁻ causes the hyper-polarization of the membrane, leading to inhibitory actions.

GABRA2 increases the risk of anxiety making it a target for treating behavioral disorders.^[8] Some examples of behavioral disorders include anxiety, alcohol dependence, and drug use. GABRA2 is a binding site for benzodiazepines. Benzodiazepines are psychoactive drugs known to reduce anxiety. Benzodiazepines bind to GABRA2 causing chloride channels to open, leading to the hyper-polarization of the membrane.^[9] Other anxiolytic drugs like Diazepam target this alpha subunit in GABA-A to induce inhibitory effects.^[6]

GABRA2 is associated with reward behavior when it activates the insula.^[8] The insula is part of the cerebral cortex responsible for emotions. GABRA2 role in reward behavior explains the higher risk of alcohol dependence and drug use behavior.

Clinical significance

Since GABRA 2 mediates anxiolytic activity, it is a key receptor for emotional control. Several developmental stages of GABRA2 have shown effects on behavior such as adult alcohol dependence and adolescent behavior.

Alcoholism

This is a representation of alcohol's effects on GABA receptors and glutamate receptors.

Since GABRA 2 subunit mediates anxiolytic activity, long term use or withdrawal of ethanol can cause dependence alterations in the GABA-A receptor.^[6]

When alcohol is present in the brain, it affects two types of receptors: GABA-A, inhibitory receptors, and Glutamate, excitatory receptors. In GABA receptors, alcohol substrates bind allosterically, which allows the GABA receptors to increase their inhibitory activity. Besides giving GABA receptors an extra inhibitory punch, alcohol substrates bind to glutamate receptors, which blocks its excitatory activity. Alcohol effects on both of these metabolic pathways obstruct the brain from making memories, making well thought out decisions, and controlling impulses after long term use.^[10]

Collaborative Study on Genetics of Alcoholism (COGA) identified alcohol dependence on chromosome 4p, where SNP genotyping, and measurement of genetic variation, found GABRA2's association with alcoholism within European and African ancestries. Most of these findings were strongly associated with early alcohol use and along with drug dependence. Besides these findings, COGA investigators identified GABRA2 associated with impulsiveness and found other phenotypes affected by alcohol such as EEG-β.^[11]

Adolescent behavior

The International Behavioural and Neural Genetics Society reviewed studies that found a linkage between β1-subunits in GABA-A receptors and excitability in the reward sensitivity behavior brain region. The linkage between these two suggests that inadequate GABRA2 variants can cause the development of mental disorders, such as addiction. The addictive behaviors can be seen as aggressive and defiant, but most of these behaviors can be caused by both genetic and environmental factors.^[12]

GABRA2 genes have been linked to various behavioral traits, such as an absence of impulse control. At least 11 single nucleotide polymorphisms, or SNPs, within the GARBRA2 gene have been correlated to impulsivity and four of which were also found in alcoholism. There was an elevated neuronal activation in the insula and the Nucleus accumbens.^[12] In animals, such as rats, a relationship was found between elevated alcohol consumption and increased impulsivity to those exposed to stress at an early stage in life. This impulsivity can be reversed with pharmacological handling of GABA-A receptors containing GABRA2 in certain neurological areas.^[12]

See also

• GABA_A receptor

References

1. GRCh38: Ensembl release 89: ENSG00000151834 – Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "GABRA2 gamma-aminobutyric acid type A receptor alpha2 subunit [Homo sapiens (human)]". Gene - NCBI.
5. "Entrez Gene: GABRA2 gamma-aminobutyric acid (GABA) A receptor, alpha 2".
6. Hanns S, Möhler H (2007). The GABA Receptor. New York: Humana Press. pp. 23–31, 69–87, 87–111. ISBN 978-1-59745-465-0.
7. Enoch MA (July 2008). "The role of GABA(A) receptors in the development of alcoholism". Pharmacology Biochemistry and Behavior. New Insights Into the Function of GABAA Receptor Subtypes. 90 (1): 95–104. doi:10.1016/j.pbb.2008.03.007. PMC 2577853. PMID 18440057.
8. Engin E, Liu J, Rudolph U (November 2012). "α2-containing GABA(A) receptors: a target for the development of novel treatment strategies for CNS disorders". Pharmacology & Therapeutics. 136 (2): 142–152. doi:10.1016/j.pharmthera.2012.08.006. PMC 3478960. PMID 22921455.
9. Nuss P (2015-01-17). "Anxiety disorders and GABA neurotransmission: a disturbance of modulation". Neuropsychiatric Disease and Treatment. 11: 165–175. doi:10.2147/NDT.S58841. PMC 4303399. PMID 25653526.
10. Sullivan EV, Harris RA, Pfefferbaum A (2010). "Alcohol's effects on brain and behavior". Alcohol Research & Health. 33 (1–2): 127–143. PMC 3625995. PMID 23579943.
11. Edenberg HJ, Foroud T (August 2013). "Genetics and alcoholism". Nature Reviews. Gastroenterology & Hepatology. 10 (8): 487–494. doi:10.1038/nrgastro.2013.86. PMC 4056340. PMID 23712313.
12. Stephens DN, King SL, Lambert JJ, Belelli D, Duka T (January 2017). "GABAA receptor subtype involvement in addictive behaviour". Genes, Brain and Behavior. 16 (1): 149–184. doi:10.1111/gbb.12321. PMID 27539865.

Further reading

• Engin E, Liu J, Rudolph U (November 2012). "α2-containing GABA(A) receptors: a target for the development of novel treatment strategies for CNS disorders". Pharmacology & Therapeutics. 136 (2): 142–152. doi:10.1016/j.pharmthera.2012.08.006. PMC 3478960. PMID 22921455.
• Matthews AG, Hoffman EK, Zezza N, Stiffler S, Hill SY (September 2007). "The role of the GABRA2 polymorphism in multiplex alcohol dependence families with minimal comorbidity: within-family association and linkage analyses". Journal of Studies on Alcohol and Drugs. 68 (5): 625–633. doi:10.15288/jsad.2007.68.625. PMC 3285563. PMID 17690794.
• Drgon T, D'Addario C, Uhl GR (December 2006). "Linkage disequilibrium, haplotype and association studies of a chromosome 4 GABA receptor gene cluster: candidate gene variants for addictions". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 141B (8): 854–860. doi:10.1002/ajmg.b.30349. PMC 3922197. PMID 16894595.
• Agrawal A, Edenberg HJ, Foroud T, Bierut LJ, Dunne G, Hinrichs AL, Nurnberger JI, Crowe R, Kuperman S, Schuckit MA, Begleiter H, Porjesz B, Dick DM (September 2006). "Association of GABRA2 with drug dependence in the collaborative study of the genetics of alcoholism sample". Behavior Genetics. 36 (5): 640–650. doi:10.1007/s10519-006-9069-4. PMID 16622805. S2CID 7491312.
• Dick DM, Bierut L, Hinrichs A, Fox L, Bucholz KK, Kramer J, Kuperman S, Hesselbrock V, Schuckit M, Almasy L, Tischfield J, Porjesz B, Begleiter H, Nurnberger J, Xuei X, Edenberg HJ, Foroud T (July 2006). "The role of GABRA2 in risk for conduct disorder and alcohol and drug dependence across developmental stages". Behavior Genetics. 36 (4): 577–590. doi:10.1007/s10519-005-9041-8. PMID 16557364. S2CID 15513277.
• Tian H, Chen HJ, Cross TH, Edenberg HJ (June 2005). "Alternative splicing and promoter use in the human GABRA2 gene". Brain Research. Molecular Brain Research. 137 (1–2): 174–183. doi:10.1016/j.molbrainres.2005.03.001. PMID 15950776.
• 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. PMID 15033447.
• Edenberg HJ, Dick DM, Xuei X, Tian H, Almasy L, Bauer LO, Crowe RR, Goate A, Hesselbrock V, Jones K, Kwon J, Li TK, Nurnberger JI, O'Connor SJ, Reich T, Rice J, Schuckit MA, Porjesz B, Foroud T, Begleiter H (April 2004). "Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations". American Journal of Human Genetics. 74 (4): 705–714. doi:10.1086/383283. PMC 1181946. PMID 15024690.
• Bonnert TP, McKernan RM, Farrar S, le Bourdellès B, Heavens RP, Smith DW, Hewson L, Rigby MR, Sirinathsinghji DJ, Brown N, Wafford KA, Whiting PJ (August 1999). "theta, a novel gamma-aminobutyric acid type A receptor subunit". Proceedings of the National Academy of Sciences of the United States of America. 96 (17): 9891–9896. Bibcode:1999PNAS...96.9891B. doi:10.1073/pnas.96.17.9891. PMC 22306. PMID 10449790.
• Russek SJ (February 1999). "Evolution of GABA(A) receptor diversity in the human genome". Gene. 227 (2): 213–222. doi:10.1016/S0378-1119(98)00594-0. PMID 10023064.
• 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. PMID 8391122.
• 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. PMID 8175718.

External links

• GABRA2+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.