Gamma-aminobutyric acid type A receptor subunit alpha 4 (GABRA4)

Gamma-aminobutyric acid type A receptor subunit alpha 4 (GABRA4) is a protein-coding gene that forms an essential subunit of the heteropentameric GABA-A receptor, the primary inhibitory neurotransmitter receptor in the central nervous system [UniProt: P48050]. Unlike common alpha-1 or alpha-2 subunits, GABRA4 is frequently found in extrasynaptic locations, where it typically partners with delta subunits to mediate 'tonic' inhibition, providing a persistent inhibitory tone that regulates overall neuronal firing thresholds [PubMed: 15710646]. A key pharmacological hallmark of GABRA4-containing receptors is their relative insensitivity to classical benzodiazepines, while they remain highly responsive to neurosteroids, ethanol, and the selective agonist gaboxadol [PubMed: 21151122, PubChem: CID 3411]. The subunit plays a significant role in the neurobiology of epilepsy, alcohol use disorder, and premenstrual dysphoric disorder, as its expression is dynamically regulated by fluctuations in progesterone-derived neurosteroids [PubMed: 12480678]. Consequently, GABRA4 is considered a high-interest target for developing novel therapeutics that can precisely tune brain excitability and treat mood or seizure disorders without the side-effect profile of broad-spectrum GABAergic drugs [IUPHAR: GABRA4].

Other names

GABA(A) receptor subunit alpha-4GABA receptor alpha-4 subunitGamma-aminobutyric acid receptor subunit alpha-4GABRA4

Positive allosteric modulation or direct agonism of the GABA-A receptor complex, increasing chloride ion influx and causing neuronal hyperpolarization, specifically mediating extrasynaptic tonic inhibition [PubMed: 15710646, IUPHAR].