GABAa

GABAA receptors are a family of ligand-gated ion channels that mediate the majority of fast inhibitory neurotransmission in the mammalian central nervous system. They form a chloride-selective channel that reduces neuronal excitability when activated. The receptor is pentameric, comprising five subunits arranged to create a central pore. Subunit families include alpha (1–6), beta (1–3), gamma (1–3), delta, and others. The most common adult form is α1β2γ2, but numerous subunit combinations exist, producing variations in localization and pharmacology. Each subunit has an extracellular N-terminus that binds GABA and four transmembrane segments.

When GABA binds to the receptor’s extracellular domain, the chloride channel opens, allowing Cl− ions to enter the neuron and hyperpolarize the membrane. This inhibits action potential generation. Synaptic GABAA receptors produce phasic inhibition, while extrasynaptic receptors contribute to tonic inhibition and maintain baseline inhibitory tone. The receptors are widely distributed in the brain and spinal cord.

Pharmacologically, GABAA receptors are targets for several drug classes. Benzodiazepines and related drugs are positive allosteric modulators that bind at the interface between alpha and gamma subunits, enhancing GABA’s effects and increasing channel opening. Barbiturates increase the duration of channel openings and can activate the receptor at higher concentrations. Z-drugs (such as zolpidem) preferentially modulate α1-containing receptors and are used for hypnotic purposes. Flumazenil is a competitive antagonist at the benzodiazepine site. Neurosteroids and some endogenous modulators also influence GABAA receptor activity.

Genetic mutations in GABRA1, GABRB3, and GABRG2 have been linked to epilepsy and related neurodevelopmental disorders. In development, GABA can be depolarizing due to the immature chloride gradient governed by transporters such as NKCC1 and KCC2, transitioning to hyperpolarizing as maturation proceeds.