GABRA2

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. 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. One such benzodiazepine, Clobazam, targets 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. 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. 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. 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. == Ligands ==

Positive allosteric modulators Selective positive allosteric modulators of the α2-containing GABA-A receptor produce anxioselective effects. • Alpidem • Clobazam • TPA-023 • L-838,417 == See also ==