1.A.9.5.1
γ-Aminobutyric acid (GABA)-inhibited chloride channel. 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).