The general anesthetic etomidate and fenamate mefenamic acid oppositely affect GABA A R and GlyR: a structural explanati
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ORIGINAL ARTICLE
The general anesthetic etomidate and fenamate mefenamic acid oppositely affect GABAAR and GlyR: a structural explanation Alexey Rossokhin1 Received: 27 June 2020 / Revised: 3 September 2020 / Accepted: 7 September 2020 © European Biophysical Societies’ Association 2020
Abstract 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 G ABAARs 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 A rg19′ and G ln−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 A rg19′ side chain from the interface. Our models allow us to explain the lack of GlyR potentiation in our electrophysiological experiments. Keywords Glycine receptor · GABAAR · Etomidate · Mefenamic acid · Potentiation · Modeling
Introduction Glycine and γ-aminobutyric acid (GABA) act as inhibitory neurotransmitters in the mammalian nervous system. Inhibition in the central nervous system (CNS) is mediated by ionotropic GABAA and glycine receptors ( GABAARs and GlyRs). GABAARs are widespread in all regions of the brain. Although GlyRs have been previously thought to predominate mainly in the spinal cord and brainstem (Legendre 2001; Lynch 2009), more recent studies have shown that these receptors are also expressed in different regions of the forebrain (Aroeira et al. 2011; Jonsson et al. 2012). GABAARs and GlyRs belong to the cys-loop receptor family. Both types of receptors consist of five subunits that are symmetrically or pseudo-symmetrically (depending on
* Alexey Rossokhin [email protected] 1
Research Center of Neurology, Moscow, Russia
the homo- or hetero-oligomeric receptor structure) arranged around a central axis, forming an ion conducting pore. GABAARs are formed by
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