GABRA2

Structure

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. 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, Diazepam, 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.

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.

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

References

References

1. "GABRA2 gamma-aminobutyric acid type A receptor alpha2 subunit [Homo sapiens (human)]". Gene - NCBI.
2. "Entrez Gene: GABRA2 gamma-aminobutyric acid (GABA) A receptor, alpha 2".
3. (2007). "The GABA Receptor". Humana Press.
4. (July 2008). "The role of GABA(A) receptors in the development of alcoholism". Pharmacology Biochemistry and Behavior.
5. (November 2012). "α2-containing GABA(A) receptors: a target for the development of novel treatment strategies for CNS disorders". Pharmacology & Therapeutics.
6. (2015-01-17). "Anxiety disorders and GABA neurotransmission: a disturbance of modulation". Neuropsychiatric Disease and Treatment.
7. (2010). "Alcohol's effects on brain and behavior". Alcohol Research & Health.
8. (August 2013). "Genetics and alcoholism". Nature Reviews. Gastroenterology & Hepatology.
9. (January 2017). "GABAA receptor subtype involvement in addictive behaviour". Genes, Brain and Behavior.
10. Atack, John R.. (2011). "GABAA receptor subtype-selective modulators. I. α2/α3-selective agonists as non-sedating anxiolytics". Current Topics in Medicinal Chemistry.