Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors

Abstract

Glycine receptors (GlyR) are inhibitory Cys-loop ion channels that contribute to the control of excitability along the central nervous system (CNS). GlyR are found in the spinal cord and brain stem, and more recently they were reported in higher regions of the CNS such as the hippocampus and nucleus accumbens. GlyR are involved in motor coordination, respiratory rhythms, pain transmission, and sensory processing, and they are targets for relevant physiologic and pharmacologic modulators. Several studies with protein crystallography and cryoelectron microscopy have shed light on the residues and mechanisms associated with the activation, blockade, and regulation of pentameric Cys-loop ion channels at the atomic level. Initial studies conducted on the extracellular domain of acetylcholine receptors, ion channels from prokaryote homologs-Erwinia chrysanthemi ligand-gated ion channel (ELIC), Gloeobacter violaceus ligand-gated ion channel (GLIC)-and crystallized eukaryotic receptors made it possible to define the overall structure and topology of the Cys-loop receptors. For example, the determination of pentameric GlyR structures bound to glycine and strychnine have contributed to visualizing the structural changes implicated in the transition between the open and closed states of the Cys-loop receptors. In this review, we summarize how the new information obtained in functional, mutagenesis, and structural studies have contributed to a better understanding of the function and regulation of GlyR.

<p>A Review of Scientific Evidence for THC:CBD Oromucosal Spray (Nabiximols) in the Management of Chronic Pain</p>

“…36,48,49 At micromolar/sub-micromolar concentrations, CBD blocks equilibrative nucleoside transporters that mediate the transport of nucleosides, nucleobases and therapeutic analogs; 50 modulates the transient receptor potential of the melastatin type 8 ion channel which is the primary cold sensor in humans; 51 and modulates the orphan G-protein-coupled receptor GPR55, a probable lysophosphatidylinositol receptor involved in multiple physiological and pathophysiological pathways. 52 In addition, CBD enhances the activity of 5-HT 1a receptors which are key mediators of anxiety and depression-like behaviors; 53 enhances the activity of α1 and α3 glycine receptors whose inhibitory actions contribute to control of excitability within the central nervous system; 54 and modulates the activity of transient receptor potential ankyrin type 1 channels which play a critical role in cortical spreading depression and are a target for pain management. 55 CBD has bidirectional effects on intracellular calcium ions, and is a potent antioxidant.…”

The Glycine Receptor—A Functionally Important Primary Brain Target of Ethanol

“…EtOH binds to certain amino acids in the transmembrane domains 2 and 3 (TM2 to 3) (Förstera et al., ) and these sites are shared with those of general anesthetics (Lobo et al., ); alanine 52 (in the N‐terminal), serine 267 (TM2) and alanine 288 (TM3) are thus vital for EtOH modulation of the GlyR at a high concentration (Crawford et al., ; Mihic et al., ). This hypothesis was later supported by structural studies; for a review, see Burgos and colleagues (). EtOH interacts with surrounding amino acids forming a binding site, also called “pocket.” Yet, as EtOH's binding is distinct from classical receptor–ligand binding by high‐affinity CNS active medications, experts in the field favor the terms “action sites” and “action pockets” rather than “binding sites” (Perkins et al., ).…”

“…Subtype specific antagonists are not identified to date, yet there are indications, for example, that cyclothiazide inhibits α2‐GlyRs in a specific manner (Zhang et al, ). GlyRs are most densely expressed in the spinal cord, brain stem, retina, and cerebellum, modulating functions like respiration, sensory processing, and motor control (Betz et al., ; Burgos et al., ). More recently, GlyRs in forebrain regions, for example, the amygdala and nAc, have gained increasing interest (see below).…”

Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain

“…Recent structural data has revealed a conserved cylinder-shape architecture for all pLGICs, in which five subunits are arranged around a central five-fold axis. Each subunit comprises a large extracellular domain (ECD) which contains the agonist-binding site, four transmembrane domains (TM1-4) which shape the ion pore, a large intracellular domain (ICD) between TM3 and TM4, and a short extracellular C-terminal region (Figure 1) (Nys et al, 2013;Burgos et al, 2016;Gielen and Corringer, 2018). The binding of the agonist to the orthosteric site within the ECD triggers a rapid isomerization (i.e., gating) that results FIGURE 1 | Binding sites of analgesic compounds on pLGIC structures.…”