1.A.9.5.1
γ-Aminobutyric acid (GABA)-inhibited chloride channel, GABARA1 or GABAAR. The major central endocannabinoid, 2-arachidonoyl glycerol (2-AG), directly acts at GABA(A) receptors. It potentiates the receptor at low GABA concentrations (Sigel et al., 2011). Hydrophobic anions potently and uncompetitively antagonize GABA (A) receptor function (Chisari et al., 2011). Regulated by neurosteroids; activated by pregnenolone and allopregnenalone (Costa et al., 2012). Different subunits contribute asymmetrically to channel conductances via residues in the extracellular domain (Moroni et al., 2011). Potentiated by general anaesthetics (Nury et al., 2011). Direct physical coupling between the GABA-A receptor and the KCC2 chloride transporter underlies ionic plasticity in cerebellar purkinje neurons in response to brain-derived neurotrophic factor (BDNF) (Huang et al. 2013).  GABA type A receptors, the brain's major inhibitory neurotransmitter receptors, are the targets for many general anesthetics, including volatile anesthetics, etomidate, propofol, and barbiturates.  Anesthetics usually bind at intersubunit sites (Chiara et al. 2013). Etomidate and propofol are potent general anesthetics that act via GABAA receptor allosteric co-agonist sites located at transmembrane beta+/alpha- inter-subunit interfaces. In heteromeric receptors, betaN265 (M2-15') on beta2 and beta3 subunits are important determinants of sensitivity to these drugs (Stewart et al. 2014). A P302L mutation in the gamma2 (γ2) subunit (Dravet syndrome in humans) of the mouse when expressed with the α1 and β3 subunits, produced a 90% decrease in conductance due to slow activation and enhance desensitization. It shifted the channel to a low-conductance state by reshaping the hour-glass-like pore cavity during transitions between closed, open, and desensitized states (Hernandez et al. 2017). Numerous postive and negative allosteric modulators have been identified (Maldifassi et al. 2016). Crystal structures of neurosteroids bound to alpha homopentameric GABAARs have revealed binding to five equivalent sites (Alvarez and Pecci 2018). Masiulis et al. 2019 reported high-resolution cryo-EM structures in which the full-length human alpha1beta3gamma2L GABAA receptor in lipid nanodiscs is bound to (1) the channel-blocker picrotoxin, (2) the competitive antagonist bicuculline, (3) the agonist GABA, and (4 AND 5) the classical benzodiazepines alprazolam and diazepam. They described the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABAA receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region (Masiulis et al. 2019). Rare variants in the ε-subunit have been identified in patients with a wide spectrum of epileptic phenotypes (Markus et al. 2020). Many (but not all) sedative-hypnotics are capable of positively modulating the GABAA receptor by binding within a common set of hydrophobic cavities (McGrath et al. 2020). Isoflurane binds to a site within the transmembrane domains of the receptor and suggest functional similarity between the GABA(A) alpha-1, -2, and -3 subunits (Schofield and Harrison 2005). Mutations ain the M2 and M3 TMSs of the GABAARs alpha1 and beta2 subunits affect late gating transitions including opening/closing and desensitization (Terejko et al. 2021). The distance between an alpha1beta3gamma2L GABA type A receptor residue and the drug, etomidate, when bound in the transmembrane beta+/alpha- interface, has been determined (Fantasia et al. 2021). There is a binding site in the beta(+)alpha(-) interface for the anesthetic, propofol (Borghese et al. 2021). Delta selective compound 2 (DS2; 4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridin-3-yl]benzamide) is widely used to study selective actions mediated by delta-subunit-containing GABAA receptors. The molecular determinants responsible for positive modulation by DS2 have been identified (Falk-Petersen et al. 2021). Two high-resolution structures of GABAA receptors in complex with zolpidem, a positive allosteric modulator and heavily prescribed hypnotic, and DMCM, a negative allosteric modulator with convulsant and anxiogenic properties. These two drugs share the extracellular benzodiazepine site at the alpha/gamma subunit interface and two transmembrane sites at beta/alpha interfaces. Structural analyses reveal a basis for the subtype selectivity of zolpidem that underlies its clinical success (Zhu et al. 2022). Molecular dynamics simulations provided insight into how DMCM switches from a negative to a positive modulator as a function of binding site occupancy (Zhu et al. 2022). Avermectin-imidazo[1,2-a]pyridine hybrids are potent GABAA receptor modulators (Volkova et al. 2022). Clptm1 is a target for suppressing epileptic seizures by regulating GABA(A) R-mediated inhibitory synaptic transmission in a PTZ-induced epilepsy model (Zhang et al. 2023). The allosteric modulation of α1β3γ2 GABA(A) receptors by farnesol through neurosteroid sites has been characterized (Gc et al. 2023). Chloride ion dysregulation in epileptogenic neuronal networks has been reviewed (Weiss 2023). Mutation of valine 53 at the interface between extracellular and transmembrane domains of the beta(2) principal subunit affects the GABA(A) receptor gating has beeen examined (Kłopotowski et al. 2023). Acrylamide-derived modulators of the GABA(A) receptor have been described (Arias et al. 2023).  Resting-state alterations in behavioral variant frontotemporal dementia are related to the distribution of monoamine and GABA neurotransmitter systems (Hahn et al. 2024).