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

Abstract

Background γ-Aminobutyric acid sub-type A receptors (GABAARs) 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 GABAARs 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 GABAARs 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 GABAA 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 GABAA receptors in detail. Accordingly, this review aims to summarize the current understanding of the structural, physiological, and pharmacological properties of GABAARs, as well as shedding light on the most common associated disorders.

The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy

“…GABA acts through the activation of GABA A (a ligand-gated ion channel) and GABA B (a G-protein-coupled channel) receptors. GABA A activation leads to a rapid increase in the flow of chloride post-synaptically and is the base of action of first choice antiepileptic drugs such as barbiturates and benzodiazepines [ 98 ]; while antagonists of GABA A , such as bicuculline and picrotoxin, are proconvulsivants [ 99 ]. In humans, GABA concentrations or GABA-receptor densities have been found to be reduced in epileptic patients [ 100 , 101 ], and reduced binding to benzodiazepines has been demonstrated in the mesial temporal lobe on positron emission tomographic scanning [ 102 , 103 ] meaning reduced inhibitory capacity and responsiveness to pharmacological activation.…”

GABAA Receptor Variants in Epilepsy

“…For instance, receptors containing α1-3, β1-3, and 2 subunits are typically localized in the postsynaptic sites, where a high concentration of GABA can open the receptor leading to the increase of anion conductance in a short time period. On the other hand, receptors containing α4-6, β2/3, and  subunits are localized in the extrasynaptic sites, and they have high GABA affinity, but low desensitization time compared with postsynaptic GABAARs (17). The most prominent population of GABAAR subtypes in mammalian brains are the combination of α1, β2/3, and 2 subunits.…”

“…Each subunit shares common structural motifs with a relatively long extracellular N-terminal domain (NTD), four transmembrane helices domain (TM1-4), an extended intracellular cytoplasmic domain (ICD) between TM3 and TM4, and a short extracellular C-terminus (Figure 1B). The long NTD plays an important role in binding agonists, antagonists, and benzodiazepines (BZDs) (17).…”

Ligand-Gated Ion Channels as Targets for Treatment and Management of Cancers

“…Even within the GABA A R subtype there exists significant compositional heterogeneity as 19 receptor subtype genes have been identified in humans, coding for six α, three β, three γ, three ρ, one δ, one ε, one π, and one θ-subunit ( Sigel and Steinmann, 2012 ; Ghit et al, 2021 ). The most common adult human assembly is of a hetero-pentamer consisting of two α, two β, and one γ-subunit encoded by GABR genes GABRA , GABRB , and GABRG , respectively.…”