GABRA2 explained

Gamma-aminobutyric acid receptor subunit alpha-2 is a protein in humans that is encoded by the GABRA2 gene.^[1]

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.^[2] This receptor is found mainly in specific regions of the brain, such as the hippocampus.^[3]

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.^[4] 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

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. 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. 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.

Function

GABRA2 mediates neural activity necessary for information processing in inter-neurons. 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.^[5] 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.^[6] Other anxiolytic drugs like Diazepam target this alpha subunit in GABA-A to induce inhibitory effects.

GABRA2 is associated with reward behavior when it activates the insula. 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

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

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.^[7]

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.^[8]

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.^[9]

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. 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.

See also

• GABA_A receptor

Further reading

• Engin E, Liu J, Rudolph U . α2-containing GABA(A) receptors: a target for the development of novel treatment strategies for CNS disorders . Pharmacology & Therapeutics . 136 . 2 . 142–152 . November 2012 . 22921455 . 10.1016/j.pharmthera.2012.08.006 . 3478960.
• Matthews AG, Hoffman EK, Zezza N, Stiffler S, Hill SY . 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 . September 2007 . 17690794 . 3285563 . 10.15288/jsad.2007.68.625.
• Drgon T, D'Addario C, Uhl GR . 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 . December 2006 . 16894595 . 10.1002/ajmg.b.30349 . 3922197 .
• 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 . Association of GABRA2 with drug dependence in the collaborative study of the genetics of alcoholism sample . Behavior Genetics . 36 . 5 . 640–650 . September 2006 . 16622805 . 10.1007/s10519-006-9069-4 . 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 . The role of GABRA2 in risk for conduct disorder and alcohol and drug dependence across developmental stages . Behavior Genetics . 36 . 4 . 577–590 . July 2006 . 16557364 . 10.1007/s10519-005-9041-8 . 15513277 .
• Tian H, Chen HJ, Cross TH, Edenberg HJ . Alternative splicing and promoter use in the human GABRA2 gene . Brain Research. Molecular Brain Research . 137 . 1–2 . 174–183 . June 2005 . 15950776 . 10.1016/j.molbrainres.2005.03.001 .
• Chou KC . Modelling extracellular domains of GABA-A receptors: subtypes 1, 2, 3, and 5 . Biochemical and Biophysical Research Communications . 316 . 3 . 636–642 . April 2004 . 15033447 . 10.1016/j.bbrc.2004.02.098 .
• 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 . 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 . April 2004 . 15024690 . 1181946 . 10.1086/383283 .
• 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 . 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 . August 1999 . 10449790 . 22306 . 10.1073/pnas.96.17.9891 . 1999PNAS...96.9891B . free .
• Russek SJ . Evolution of GABA(A) receptor diversity in the human genome . Gene . 227 . 2 . 213–222 . February 1999 . 10023064 . 10.1016/S0378-1119(98)00594-0 .
• Hadingham KL, Wingrove P, Le Bourdelles B, Palmer KJ, Ragan CI, Whiting PJ . 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 . June 1993 . 8391122 .
• Tögel M, Mossier B, Fuchs K, Sieghart W . 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 . April 1994 . 10.1016/S0021-9258(18)99974-6 . 8175718 . free .

Notes and References

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