GABA and glycine act as inhibitory neurotransmitters in the CNS. Inhibitory neurotransmission is mediated via activation of ionotropic GABAA and glycine receptors. We used a modeling approach to explain the opposite effects of the general anesthetic etomidate (ETM) and fenamate mefenamic acid (MFA) on GABA- and glycine-activated currents recorded in isolated cerebellar Purkinje cells and hippocampal pyramidal neurons, respectively. These drugs potentiated GABAARs but blocked GlyRs. We built a homology model of α1β GlyR based on the cryo-EM structure of open α1 GlyR, used the α1β3γ2 GABAAR structure from the PDB, and applied Monte-Carlo energy minimization to optimize models of receptors and ligand-receptor complexes. In silico docking suggests that ETM/MFA bind at the transmembrane β( +)/α( -) intersubunit interface in GABAAR. Our models predict that the bulky side chain of the highly conserved Arg19' residue at the plus interface side wedges the interface and maintains the conducting receptor state. We hypothesized that MFA/ETM binding at the β( +)/α( -) interface leads to prolongation of receptor life-time in the open state. Having analyzed different GABAAR and GlyR structures available in the PDB, we found that mutual arrangement of the Arg19' and Gln-26' side chains at the plus and minus interface sides, respectively, plays an important role when the receptor switches from the open to closed state. We show that this process is accompanied by narrowing of the intersubunit interfaces, leading to extrusion of the Arg19' side chain from the interface. Our models allow us to explain the lack of GlyR potentiation in our electrophysiological experiments.
Keywords: Etomidate; GABAAR; Glycine receptor; Mefenamic acid; Modeling; Potentiation.