GABAA receptors: structure, function, pharmacology, and related disorders

Abstract

Background: γ-Aminobutyric acid sub-type A receptors (GABA_ARs) are the most prominent inhibitory neurotransmitter receptors in the CNS. They are a family of ligand-gated ion channel with significant physiological and therapeutic implications.

Main body: GABA_ARs are heteropentamers formed from a selection of 19 subunits: six α (alpha1-6), three β (beta1-3), three γ (gamma1-3), three ρ (rho1-3), and one each of the δ (delta), ε (epsilon), π (pi), and θ (theta) which result in the production of a considerable number of receptor isoforms. Each isoform exhibits distinct pharmacological and physiological properties. However, the majority of GABA_ARs are composed of two α subunits, two β subunits, and one γ subunit arranged as γ2β2α1β2α1 counterclockwise around the center. The mature receptor has a central chloride ion channel gated by GABA neurotransmitter and modulated by a variety of different drugs. Changes in GABA synthesis or release may have a significant effect on normal brain function. Furthermore, The molecular interactions and pharmacological effects caused by drugs are extremely complex. This is due to the structural heterogeneity of the receptors, and the existence of multiple allosteric binding sites as well as a wide range of ligands that can bind to them. Notably, dysfunction of the GABAergic system contributes to the development of several diseases. Therefore, understanding the relationship between GABA_A receptor deficits and CNS disorders thus has a significant impact on the discovery of disease pathogenesis and drug development.

Conclusion: To date, few reviews have discussed GABA_A receptors in detail. Accordingly, this review aims to summarize the current understanding of the structural, physiological, and pharmacological properties of GABA_ARs, as well as shedding light on the most common associated disorders.

Keywords: Allosteric modulation; Alzheimer’s disease; Autism spectrum disorder; Barbiturates; Benzodiazepine; Epilepsy; GABA; GABAAR; Schizophrenia.

Fig. 1

Schematic representation of GABA_A receptor structure. (A) GABA_A receptors are heteropentamers that form a chloride-ion-permeable channel. They are formed by 19 subunits: α1–6, β1–3, γ1–3, δ, ε, θ, π, and ρ1–3. The GABA binding sites are located at the junction of β+/α−, whereas benzodiazepines (BZs) are located at α+/γ− interface. Anesthetics are located at different sites where barbiturates bind to α+/β−, and γ+/β− interfaces while etomidate binds to β+/α− interface. The binding site of the neurosteroids is located at α subunit as well as the β+/α− interface. (B) The most popular GABA_AR isoform is composed of α1, β2, and γ2 subunits arranged γ2β2α1β2α1 counterclockwise around the central pore. (C) The mature subunit contains a large hydrophilic extracellular N-terminal, four hydrophobic transmembrane domains (TMD: TM1–TM4), and a small extracellular C terminus. TM1 and TM2 are connected by a short intracellular loop while a short extracellular loop connects TM2 and TM3. Besides, TM3 and TM4 are connected by a lengthy intracellular loop that can be phosphorylated

Fig. 2

Schematic illustration of GABA shunt. Transamination of α-ketoglutarate by GABA-α ketoglutarate transaminase (GABA-T) to produce glutamate which is decarboxylated to GABA by glutamic acid decarboxylase (GAD). GABA-T metabolizes GABA to succinic semialdehyde which is oxidized to succinate by succinic semialdehyde dehydrogenase (SSADH). Then, succinate can enter the Krebs cycle and complete the loop