GABRA2
Gamma-aminobutyric acid receptor subunit alpha-2 is a protein that in humans is encoded by the GABRA2 gene.[4]
GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified.[5] A receptor is typically made of two alpha, two beta, and one gamma subunit. It is found mainly in specific regions of the brain.[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]
Function
The GABAA receptor has two alpha, two beta, and one gamma subunits that form a gated ion channel. GABRA2 is present at high levels when there are only low levels of GABRA1. Alpha-2 subunit increases the risk of anxiety making it a target for treating behavioral disorders.[8] GABRA2 subunit has a binding site for benzodiazepines known to reduce anxiety. Anxiolytic drugs like Diazepam target this alpha subunit in GABAA to induce inhibitory actions.[6] GABRA2 is associated with reward behavior when it activates the insula.[8] This reward behavior explains the higher risk of alcohol dependence and drug use behavior. GABRA2 mediates neural activity necessary for information processing in inter-neurons.[6]
Structure
GABRA2 is just one subunit out of a five part pentametric form, usually bound with another alpha, two beta, and one gamma subunit.[6] It is part of one of the most common expressions (α2β3γ2) which is seen in 13% of all GABA-A receptors.[7] GABRA2 is found primarily in the brain, focused in such regions such as the hippocampus and/or forebrain. It is more confined to areas of the brain in comparison to other alpha subunits. 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]
Clinical significance
Since alpha-2GABRA 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
Since GABA(A) is an inhibitory neurotransmitter and α2-GABA(A) receptor mediates anxiolytic activity.[6] long term or withdrawal of ethanol use can cause alterations in the GABRA(A) receptor.[9][unreliable medical source] When alcohol is present in the brain, it binds to GABA receptors and making them more inhibitory and they also bind to glutamate receptors to block their excitatory activity, which affects the brain from making memories, making well thought out decisions, and controlling impulses.[10][unreliable medical source] Studies have been conducted testing how adult alcohol dependence is associated with a gene mutation in α2-GABA(A). These tests also experimented the suggestion that adult alcohol dependence is acquired from early developmental stages such as childhood conduct disorder symptoms. Although some studies identified that there was no association between α2-GABA(A) and adult alcohol dependence on adolescent sample, they did observe that after 21 years of age, subjects with no copies of α2-GABA(A)demonstrated adult alcohol dependence as those who did carry the copy.[11][unreliable medical source] This suggests that α2-GABA(A) is associated with adult alcohol dependence. Similarly, other studies have found that several genes such as rs279858 are most replicated SNP in α2-GABA(A) that are associated to adult dependence alcohol.[12][unreliable medical source]
Adolescent behavior
Studies have suggested that individuals that were previously found to be more at risk for developing alcohol dependence were individuals who also displayed maladaptive externalized behaviors more likely to carry the GABRA2 variant (rs279858).[13] The evidence suggesting that α2 containing receptors are involved in behavioral control is the aggressive behavior in mice that was induced by benzodiazepines.[13] GABRA2 genes has been to various behavioral traits such as an absence of impulse control. There have been at least 11 single nucleotide polymorphisms within the α2 gene that 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.[13] 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, but can be reversed with pharmacological handling of α2 GABA(A) receptors in certain neurological areas.[13]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000151834 – 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.
- ^ "GABRA2 gamma-aminobutyric acid type A receptor alpha2 subunit [Homo sapiens (human)]". Gene - NCBI.
- ^ "Entrez Gene: GABRA2 gamma-aminobutyric acid (GABA) A receptor, alpha 2".
- ^ a b c d e f Hanns, S.J.; Möhler, Hanns (2007). The GABA Receptor. New York: Humana Press. pp. 23–31, 69–87, 87–111. ISBN 978-1-59745-465-0.
{{cite book}}: Unknown parameter|name-list-format=ignored (|name-list-style=suggested) (help) - ^ a b 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.
- ^ a b 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): 142–52. doi:10.1016/j.pharmthera.2012.08.006. PMC 3478960. PMID 22921455.
- ^ Melroy WE, Stephens SH, Sakai JT, Kamens HM, McQueen MB, Corley RP, Stallings MC, Hopfer CJ, Krauter KS, Brown SA, Hewitt JK, Ehringer MA (2014). "Examination of genetic variation in GABRA2 with conduct disorder and alcohol abuse and dependence in a longitudinal study". Behavior Genetics. 44 (4): 356–67. doi:10.1007/s10519-014-9653-y. PMC 4098655. PMID 24687270.
- ^ Koob GF, Roberts AJ, Schulteis G, Parsons LH, Heyser CJ, Hyytiä P, Merlo-Pich E, Weiss F (1998). "Neurocircuitry targets in ethanol reward and dependence". Alcoholism, Clinical and Experimental Research. 22 (1): 3–9. doi:10.1111/j.1530-0277.1998.tb03611.x. PMID 9514280.
- ^ 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 (2006). "The role of GABRA2 in risk for conduct disorder and alcohol and drug dependence across developmental stages". Behavior Genetics. 36 (4): 577–90. doi:10.1007/s10519-005-9041-8. PMID 16557364.
- ^ Strac DS, Erjavec GN, Perkovic MN, Sviglin KN, Borovecki F, Pivac N (2015). "Association of GABAA receptor α2 subunit gene (GABRA2) with alcohol dependence-related aggressive behavior". Progress in Neuro-psychopharmacology & Biological Psychiatry. 63: 119–25. doi:10.1016/j.pnpbp.2015.06.010. PMID 26116794.
- ^ a b c d 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): 142–52. doi:10.1016/j.pharmthera.2012.08.006. 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): 625–33. 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): 854–60. doi:10.1002/ajmg.b.30349. 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): 640–50. doi:10.1007/s10519-006-9069-4. PMID 16622805.
- 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): 577–90. doi:10.1007/s10519-005-9041-8. PMID 16557364.
- 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): 174–83. 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): 636–42. 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): 705–14. 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): 9891–6. 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): 213–22. 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): 970–5. 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): 12993–8. PMID 8175718.
External links
- GABRA2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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