Gamma-aminobutyric acid type A receptor alpha1-beta3-gamma2 (GABAA receptor α1β3γ2)

The GABAA receptor α1β3γ2 is a pentameric transmembrane receptor that functions as a ligand-gated chloride ion channel. It is composed of two α1 subunits, two β3 subunits, and one γ2 subunit arranged counterclockwise around a central pore. Each subunit contains four transmembrane domains (TM1-TM4), with TM2 lining the ion channel pore. The receptor has a large extracellular N-terminal domain where GABA and benzodiazepines bind, and an intracellular domain between TM3 and TM4 that is involved in protein interactions and post-translational modifications. The α1β3γ2 combination is one of the most common GABAA receptor subtypes in the brain. When activated by the neurotransmitter GABA, the receptor undergoes a conformational change that opens the chloride channel, allowing chloride ions to flow into the neuron, resulting in hyperpolarization and inhibition of neuronal activity. This receptor subtype is the target of numerous clinically important drugs, including benzodiazepines which bind at the interface between α1 and γ2 subunits, and barbiturates which act at sites within the transmembrane domains. The gating mechanism involves electrostatic interactions between specific amino acid residues in the extracellular domain and the transmembrane domains, particularly involving the Cys-loop and loop 2 regions. The α1 subunit confers sensitivity to benzodiazepines, while the γ2 subunit is required for benzodiazepine binding and modulation. The β3 subunit contributes to the formation of the GABA binding site at the α1-β3 interface and influences channel properties.

Other names

GABAA receptorGABAAR α1β3γ2Gamma-aminobutyric acid receptor subunit combination α1β3γ2GABA(A) receptor; alpha-1/beta-3/gamma-2

Drugs targeting this receptor exert their effects primarily through allosteric modulation (positive or negative), or by acting as agonists to directly activate the channel. Positive allosteric modulators like benzodiazepines, barbiturates, and neurosteroids enhance the channel opening probability or duration in the presence of GABA, leading to increased chloride influx and inhibition. Benzodiazepines typically increase channel opening frequency, while barbiturates increase opening duration. Negative allosteric modulators or inverse agonists decrease receptor activity.