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GABRA2: https://en.wikipedia.org/wiki/GABRA2

Summary

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

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. A receptor is typically made of two alpha, two beta, and one gamma subunit. It is found mainly in specific regions of the brain.[2] 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.[3]

Function

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The GABAA receptor has six alpha subunits that function to form a gated ion channel.[4] 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.[5] 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.[2] GABRA2 is associated with reward behavior when it activates the insula.[5] 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.[2]

Structure

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Figure 1: Shows the five part subunits that typically creates a GABA-A receptor. GABRA2 is only one alpha subunit in the structure demonstrated with the color red.

GABRA2 is just one subunit out of a five part pentametric form, usually bound with another alpha, two beta, and one gamma subunit.[2] It is part of one of the most common expressions (α2β3γ2) which is seen in 13% of all GABA-A receptors.[3] GABRA2 is found primarily in the brain, focussed in such regions such as the hippocampus 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 (see clinical applications).[2]

Clinical application

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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

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Since GABA(A) is an inhibitory neurotransmitter and α2-GABA(A) receptor mediates anxiolytic activity.[2] long term or withdrawal of ethanol use can cause alterations in the GABRA(A) receptor.[6] 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.[7] 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.[8] 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.[9]

Adolescent behavior

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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).[10] The evidence suggesting that α2 containing receptors are involved in behavioral control is the aggressive behavior in mice that was induced by benzodiazepines.[10] 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.[10] 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.[10]

References

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(Studies)Mutations: Studies show that GABRA2 gene has an affect on alcoholism [1]. There are also problems in adolescent behavior when GAABRA2 is present [2]

  1. ^ Förstera, Benjamin; Castro, Patricio A.; Moraga-Cid, Gustavo; Aguayo, Luis G. (2016-05-06). "Potentiation of Gamma Aminobutyric Acid Receptors (GABAAR) by Ethanol: How Are Inhibitory Receptors Affected?". Frontiers in Cellular Neuroscience. 10. doi:10.3389/fncel.2016.00114. ISSN 1662-5102. PMC 4858537. PMID 27199667.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  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.
  3. ^ a b Enoch, Mary-Anne (2008-07-01). "The role of GABAA 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.{{cite journal}}: CS1 maint: PMC format (link)
  4. ^ "GABAA receptor". Wikipedia. 2017-02-16.
  5. ^ a b Engin, Elif; Liu, Jing; Rudolph, Uwe (2017-03-27). "α2-containing GABAA 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. ISSN 0163-7258. PMC 3478960. PMID 22921455.{{cite journal}}: CS1 maint: PMC format (link)
  6. ^ Melroy, Whitney E. et al. "Examination Of Genetic Variation In GABRA2 With Conduct Disorder And Alcohol Abuse And Dependence In A Longitudinal Study". Behavior Genetics 44.4 (2014): 356-367. Web.
  7. ^ Neurocircuitry targets in ethanol reward and dependence. G. F. Koob, A. J. Roberts, G. Schulteis, L. H. Parsons, C. J. Heyser, P. Hyytiä, E. Merlo-Pich, F. Weiss Alcohol Clin Exp Res. 1998 Feb; 22(1): 3–9.
  8. ^ Dick, Danielle M. et al. "The Role Of GABRA2 In Risk For Conduct Disorder And Alcohol And Drug Dependence Across Developmental Stages". Behavior Genetics 36.4 (2006): 577-590. Web.
  9. ^ Švob Štrac, Dubravka et al. "The GABAA Receptor Α2 Subunit Gene (GABRA2) Is Associated With Alcohol-Related Behavior". BMC Pharmacology and Toxicology 13.Suppl 1 (2012): A8. Web.
  10. ^ a b c d Stephens, D. N.; King, S. L.; Lambert, J. J.; Belelli, D.; Duka, T. (2017-01-01). "GABAA receptor subtype involvement in addictive behaviour". Genes, Brain and Behavior. 16 (1): 149–184. doi:10.1111/gbb.12321. ISSN 1601-183X.
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