γ-Aminobutyric acid (GABA)-inhibited Cl^- channel, type A (α-, β- γ-subunit precursors), GABRA2 or GABAAR2, regulated by GABA receptor accessory protein, GABARAP (Luu et al., 2006) and FRMD7 (TC# 8.A.25.1.5) (Jiang et al. 2020). A mutation in the GABAA receptor alpha 1 subunit, linked to human epilepsy, affects channel gating properties (Fisher 2004). The anti-convulsant stiripentol acts directly on the GABA(A) receptor as a positive allosteric modulator (Fisher 2009). The major central endocannabinoid, 2-arachidonoyl glycerol (2-AG), also directly acts at GABA(A) receptors to potentiate the receptor at low GABA concentrations (Sigel et al., 2011). The recpetor is also allosterically regulated by neurosteroids via TMS1 of the beta subunit (Baker et al. 2010).  General anesthetic binding site(s) have been identified (Chiara et al., 2012; Woll et al. 2018). 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). Allopregnanolone and its synthetic analog alphaxalone are GABAAR positive allosteric modulators (Yu et al. 2019). 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).  Both the alpha and beta subunits are important for activation by alcohols and anaesthetics (McCracken et al. 2010). Direct physical coupling between the GABA-A receptor (of 4 TMSs) and the KCC2 chloride transporter underlies ionic plasticity in cerebellar purkinje neurons in response to brain-derived neurotrophic factor (BDNF) (Huang et al. 2013).  An anesthetic binding site has been identified (Franks 2015). Desensitization is regulated by interactions between the second and third transmembrane segments which affect the ion channel lumen near its intracellular end. The GABAAR and GlyR pore blocker, picrotoxin (TC# 8.C.1), prevents desensitization (Gielen et al. 2015).  The mechanism of action of methaqualone (2-methyl-3-O-tolyl-4(3H)-quinazolinone, Quaalude(R)), a sedative-hypnotic and recreational drug. Methaqualone is a positive allosteric modulator (PAM) at human alpha1,2,3,5beta2,3gamma2S GABAA receptors (GABAARs) expressed, whereas it displays diverse functionalities at the alpha4,6beta1,2,3delta GABAAR subtypes, ranging from inactivity (alpha4beta1delta), through negative (alpha6beta1delta) or positive allosteric modulation (alpha4beta2delta, alpha6beta2,3delta), to superagonism (alpha4beta3delta) (Hammer et al. 2015).  The thyroid hormone L-3,5,3'-triiodothyronine (T3) inhibits GABAA receptors at micromolar concentrations and has common features with neurosteroids such as allopregnanolone (ALLOP). Westergard et al. 2015 used functional experiments on alpha2beta1gamma2 GABAA receptors to detect competitive interactions between T3 and an agonist (ivermectin, IVM) with a crystallographically determined binding site at subunit interfaces in the transmembrane domain of a homologous receptor (glutamate-gated chloride channel, GluCl). T3 and ALLOP showed competitive effects, supporting the presence of a T3 and ALLOP binding site at one or more subunit interfaces. Residues in the beta3 subunit, at or near the etomidate/propofol binding site(s), form part of the valerenic acid modulator binding pocket (Luger et al. 2015). IV general anesthetics, including propofol, etomidate, alphaxalone, and barbiturates, enhance GABAA receptor activation. These anesthetics bind in transmembrane pockets between subunits of typical synaptic GABAA receptors (Forman and Miller 2016). Carisoprodol can directly gate and allosterically modulate type A GABA (GABAA) receptors (Kumar et al. 2017). The former sedative-hypnotic and recreational drug methaqualone (Quaalude) is a moderately potent, non-selective positive allosteric modulator of GABAA receptors (GABAARs) (Hammer et al. 2015). A methaqualone analog, 2-phenyl-3-(p-tolyl)quinazolin-4(3H)-one (PPTQ) exhibits intrinsic activity at micromolar concentrations and potentiates the GABA-evoked signaling at concentrations down to the low-nanomolar range (Madjroh et al. 2018). The PPTQ binding site is allosterically linked with sites targeted by neurosteroids and barbiturates.  Anesthetic pharmacophore binding has been studied (Fahrenbach and Bertaccini 2018). GABAA receptors are modulated via several sites by GABA, benzodiazepines, ethanol, neurosteroids and anaesthetics among others. Amundarain et al. 2018 presented a model of the alpha1beta2gamma2 subtype GABAA receptor in the APO state and in complex with selected ligands, including agonists, antagonists and allosteric modulators. Sites in TMSs 2 and 3 are important for alcohol-induced conformational changes (Jung and Harris 2006). Many anesthetics and neurosteroids act through binding to the GABAAR transmembrane domainnad x-ray structures have revealed how α-xalone, a neurosteroid anaesthetic, binds and influences potentiation, activation and desensitization (Chen et al. 2018). AA29504 is an allosteric agonist and positive allosteric modulator of GABAA receptors (Olander et al. 2018). Allosteric shift analysis in mutant α1β3γ2L GABAA receptors indicates selectivity and cross-talk among intersubunit transmembrane anesthetic sites (Szabo et al. 2019). Several epilepsy-causing mutations have been identified in the genes of the α1, β3, and γ2 subunits comprising the GABAA receptor (Absalom et al. 2019). Constituents of the GABAA receptor include a transmembrane GARLH/LHFPL protein (TC# 1.A.82.1.7) and the inhibitory synaptic protein, neuroligin 2 (TC# 8.A.117.1.1) (Tomita 2019).  GABAA receptors containing mutant alpha5 and alpha1 subunits all had reduced cell surface and total cell expression with altered endoplasmic reticulum processing, impaired synaptic clustering, reduced GABAA receptor function and decreased GABA binding potency. Thus, GABRA5 is a causative gene for early onset epileptic encephalopathy (Hernandez et al. 2019).  Mutations at Gln242 or Trp246 that eliminate neurosteroid effects do not eliminate neurosteroid binding within the intersubunit site, but significantly alter the preferred orientation of the neurosteroid (Sugasawa et al. 2019). Binding sites and interactions of propanidid and AZD3043 within GABAAR have been identified (Wang et al. 2018). Clptm1 limits GABAAR forward trafficking from the ER to the plasma membrane, and it regulates inhibitory homeostatic plasticity (Ge et al. 2018). The mechanisms of potentiation and inhibition of GABAA receptors by non-steroidal anti-inflammatory drugs, niflumic and mefenamic acids, have been described (Rossokhin et al. 2019). GABAARs are targets for important classes of clinical agents (e.g., anxiolytics, anticonvulsants, and general anesthetics) that act as positive allosteric modulators (PAMs). PAMs bind selectively to a single intersubunit site in the GABAAR transmembrane domain (Jayakar et al. 2019). The gamma2 subunit is required for clustering of these receptors, for recruitment of the submembrane scaffold protein gephyrin to postsynaptic sites, and for postsynaptic function of GABAergic inhibitory synapses (Alldred et al. 2005). The fourth TMS of the gamma2 subunit is required for postsynaptic clustering, but both the major cytoplasmic loop and the fourth transmembrane domain contribute to efficient recruitment of gephyrin to postsynaptic receptor clusters and are essential for restoration of miniature IPSCs (Alldred et al. 2005). Oligomerization and cell surface expression of recombinant GABAA receptors tagged in the delta subunit have been examined (Oflaz et al. 2019). The isoxazoline ectoparasiticide, fluralaner, exerts antiparasitic effects by inhibiting the function of GABARs, but substitutions of Gly333 in TMS3 led to substantial reductions in the sensitivity to fluralaner (Yamato et al. 2020). A potent photoreactive general anesthetic with novel binding site selectivity for GABAA receptors has been identified (Shalabi et al. 2020). GABAA receptor neurosteroid binding sites have been reviewed (Alvarez et al. 2019). Missense variants in GABRA2 are associated with early infantile epileptic encephalopathy (EIEE) as well as other disorders (Sanchis-Juan et al. 2020). Elevin novel molecules, identified using reinforcement learning, showed positive allosteric modulation, with two showing 50% activation in the low micromolar range (Michaeli et al. 2020). GABAA Receptor ligands interact with binding sites in the transmembrane domain and in the extracellular domain (Iorio 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). Allopregnanolone (3alpha5alpha-P), pregnanolone), and their synthetic derivatives are potent positive allosteric modulators (PAMs) of GABAA receptors with in vivo anesthetic, anxiolytic, and anti-convulsant effects. Photoaffinity labeling procedures have been used to identify an intersubunit steroid-binding site in heteromeric GABA type A (GABAA) receptors (Jayakar et al. 2020). Diazepam binds to etomidate binding sites in the transmembrane receptor domain giving rise to antagonism (McGrath et al. 2020). The alpha1 subunit histidine 55 at the interface between the extracellular and transmembrane domains affects preactivation and desensitization of the GABAA receptor (Kaczor et al. 2021). Coordinated downregulation of KCC2 and the GABAA receptor contributes to inhibitory dysfunction during seizure induction (Wan et al. 2020). Loss of GABAergic inhibition provides a mechanism underlying GABRB2-associated neurodevelopmental disorders (El Achkar et al. 2021). GABAAR binds the anaesthetic, Propofol, to induced conformational changes (Yuan et al. 2021). Methaqualone (2-methyl-3-(o-tolyl)-quinazolin-4(3H)-one, MTQ) is a moderately potent positive allosteric modulator (PAM) of GABAA receptors (GABAARs). Several additional potent GABAAR PAMs  include 2,3-diphenylquinazolin-4(3H)-one (PPQ), 3-(2-chlorophenyl)-2-phenylquinazolin-4(3H)-one (Cl-PPQ), and others (Wang et al. 2020). Interfacial binding sites for cholesterol on GABAA receptors compete with neurosteroids (Lee 2021). GABAAR is inhibited by L-type calcium channel blockers (Das et al. 2004). In in vivo studies, Stigmasterol (0.5-3.0 mg/kg, i.p.) exerted significant anxiolytic and anticonvulsant effects in an identical manner to allopregnanolone, indicating the involvement of a GABAergic mechanism. Thus, GABAA receptors are subject to anxiolytic and anticonvulsant activities of stigmasterol. Thus, stigmasterol is a candidate steroidal drug for the treatment of neurological disorders due to its positive modulation of GABA receptors (Karim et al. 2021). Sesquiterpenes and sesquiterpenoids harbor modulatory allosteric properties that affect inhibitoryGABAA receptors (Janzen et al. 2021). High-dose benzodiazepines positively modulate GABAA receptors via a flumazenil-insensitive mechanism (Wang et al. 2021). Benzodiazepine binding to transmembrane anaesthetic binding sites of the GABAA receptor can produce positive or negative modulation manifesting as decreases or increases in locomotion, respectively. Selectivity for these sites may contribute to the distinct GABAA receptor and behavioural actions of different benzodiazepines, particularly at high anaesthetic concentrations (McGrath et al. 2021). (+)-Catharanthine potentiates the GABAA receptor by binding to a transmembrane site at the beta(+)/alpha(-) interface near the TMS2-TMS3 loop (Arias et al. 2022). Diazepam derivatives are allosteric modulators of GABAA receptor alpha1beta2gamma2 subtypes (Djebaili et al. 2022). α1 proline 277 residues regulate GABAAR gating through M2-M3 loop interactions in the interfacial region (Kaczor et al. 2022). Regulated assembly and neurosteroid modulation constrain GABA(A) receptor pharmacology in vivo (Sun et al. 2023). Pathogenic variants of the human GABRA1 gene are associated with epilepsy (Arslan 2023). Resting-state alterations in behavioral variant frontotemporal dementia are related to the distribution of monoamine and GABA neurotransmitter systems (Hahn et al. 2024). GABA-A receptor changes underpin the antidepressant response to ketamine (Wan et al. 2020). Loss of GABAergic inhibition provides a mechanism underlying GABRB2-associated neurodevelopmental disorders (El Achkar et al. 2021). GABAAR binds the anaesthetic, Propofol, to induced conformational changes (Yuan et al. 2021). Methaqualone (2-methyl-3-(o-tolyl)-quinazolin-4(3H)-one, MTQ) is a moderately potent positive allosteric modulator (PAM) of GABAA receptors (GABAARs). Several additional potent GABAAR PAMs  include 2,3-diphenylquinazolin-4(3H)-one (PPQ), 3-(2-chlorophenyl)-2-phenylquinazolin-4(3H)-one (Cl-PPQ), and others (Wang et al. 2020). Interfacial binding sites for cholesterol on GABAA receptors compete with neurosteroids (Lee 2021). GABAAR is inhibited by L-type calcium channel blockers (Das et al. 2004). In in vivo studies, Stigmasterol (0.5-3.0 mg/kg, i.p.) exerted significant anxiolytic and anticonvulsant effects in an identical manner to allopregnanolone, indicating the involvement of a GABAergic mechanism. Thus, GABAA receptors are subject to anxiolytic and anticonvulsant activities of stigmasterol. Thus, stigmasterol is a candidate steroidal drug for the treatment of neurological disorders due to its positive modulation of GABA receptors (Karim et al. 2021). Sesquiterpenes and sesquiterpenoids harbor modulatory allosteric properties that affect inhibitoryGABAA receptors (Janzen et al. 2021). High-dose benzodiazepines positively modulate GABAA receptors via a flumazenil-insensitive mechanism (Wang et al. 2021). Benzodiazepine binding to transmembrane anaesthetic binding sites of the GABAA receptor can produce positive or negative modulation manifesting as decreases or increases in locomotion, respectively. Selectivity for these sites may contribute to the distinct GABAA receptor and behavioural actions of different benzodiazepines, particularly at high anaesthetic concentrations (McGrath et al. 2021). (+)-Catharanthine potentiates the GABAA receptor by binding to a transmembrane site at the beta(+)/alpha(-) interface near the TMS2-TMS3 loop (Arias et al. 2022). Diazepam derivatives are allosteric modulators of GABAA receptor alpha1beta2gamma2 subtypes (Djebaili et al. 2022). α1 proline 277 residues regulate GABAAR gating through M2-M3 loop interactions in the interfacial region (Kaczor et al. 2022). Regulated assembly and neurosteroid modulation constrain GABA(A) receptor pharmacology in vivo (Sun et al. 2023). Pathogenic variants of the human GABRA1 gene are associated with epilepsy (Arslan 2023). Resting-state alterations in behavioral variant frontotemporal dementia are related to the distribution of monoamine and GABA neurotransmitter systems (Hahn et al. 2024). GABA-A receptor changes underpin the antidepressant response to ketamine (Sumner et al. 2024).