Gamma-aminobutyric acid type A receptor subunit alpha-1 (encoded by GABRA1) (GABA-A receptor α1 subunit (GABAA α1; GABRA1))

The Gamma-aminobutyric acid type A receptor subunit alpha-1 is the most widely expressed α subunit of the pentameric GABAA chloride channel complex and is commonly incorporated into α1β2/3γ2 assemblies in the brain. GABA binding to the extracellular sites triggers channel opening and chloride influx in mature neurons, producing fast synaptic inhibition; α1-containing receptors mediate prominent phasic inhibitory currents and define key pharmacological properties at the benzodiazepine site located at the α/γ interface. High-resolution cryo-EM structures of α1β2γ2 receptors bound to zolpidem or DMCM reveal how α1 residues confer ligand selectivity and how allosteric modulators enhance or inhibit GABA-evoked currents; endogenous neurosteroid allopregnanolone co-purifies with native α1-containing receptors, highlighting strong physiological modulation. Loss-of-function GABRA1 mutations reduce receptor surface expression/function and are implicated in absence and generalized epilepsies. GABAA receptors are heteropentamers typically containing two α, two β, and one γ subunit; native α1-containing receptors often arrange α-β-α-β-γ around the pore. The benzodiazepine site localizes at the α1/γ2 interface; zolpidem selectivity involves α1 loop C residues (e.g., V203, S205, G201) and γ2 contacts. α1-containing receptors are abundant drug targets across CNS therapeutics.

Other names

GABRA1 (gene/protein symbol)GABA-A receptor alpha1 subunit; α1 subunit of GABAA receptorGABAAR α1; GABA-A α1Note: Sometimes referenced within α1β2γ2 GABAA receptor assemblies

Positive allosteric modulation at the benzodiazepine site at the α/γ interface enhances GABA-evoked chloride currents (e.g., zolpidem), producing sedation/hypnosis/anxiolysis depending on subunit context. Negative allosteric modulation/inverse agonism at benzodiazepine site reduces channel activity, provoking anxiogenic/convulsant effects (e.g., DMCM). Orthosteric activation by GABA opens the chloride channel to hyperpolarize neurons (in adults), mediating inhibition. Neurosteroid positive allosteric modulation at transmembrane sites increases channel open probability and potentiates inhibition. Other allosteric modulators (barbiturates, anesthetics) act at distinct transmembrane interfaces to potentiate or gate the channel.