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Bioinformatics (Oxford, England) Jun 2020Glycine receptors (GlyRs) mediate fast inhibitory neurotransmission in the brain and have been recognized as key pharmacological targets for pain. A large number of...
MOTIVATION
Glycine receptors (GlyRs) mediate fast inhibitory neurotransmission in the brain and have been recognized as key pharmacological targets for pain. A large number of chemically diverse compounds that are able to modulate GlyR function both positively and negatively have been reported, which provides useful information for the development of pharmacological strategies and models for the allosteric modulation of these ion channels.
RESULTS
Based on existing literature, we have collected 218 unique chemical entities with documented modulatory activities at homomeric GlyR-α1 and -α3 and built a database named GRALL. This collection includes agonists, antagonists, positive and negative allosteric modulators and a number of experimentally inactive compounds. Most importantly, for a large fraction of them a structural annotation based on their putative binding site on the receptor is provided. This type of annotation, which is currently missing in other drug banks, along with the availability of cooperativity factors from radioligand displacement experiments are expected to improve the predictivity of in silico methodologies for allosteric drug discovery and boost the development of conformation-based pharmacological approaches.
AVAILABILITY AND IMPLEMENTATION
The GRALL library is distributed as a web-accessible database at the following link: https://ifm.chimie.unistra.fr/grall. For each molecular entry, it provides information on the chemical structure, the ligand-binding site, the direction of modulation, the potency, the 3D molecular structure and quantum-mechanical charges as determined by our in-house pipeline.
CONTACT
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Allosteric Regulation; Binding Sites; Gene Library; Ligands; Receptors, Glycine; Synaptic Transmission
PubMed: 32163115
DOI: 10.1093/bioinformatics/btaa170 -
Tidsskrift For Den Norske Laegeforening... Mar 2004Glycine is an essential component of important biological molecules, a key substance in many metabolic reactions, the major inhibitory neurotransmitter in the spinal... (Review)
Review
BACKGROUND
Glycine is an essential component of important biological molecules, a key substance in many metabolic reactions, the major inhibitory neurotransmitter in the spinal cord and brain stem, and has anti-inflammatory, cytoprotective, and immunomodulatory qualities.
MATERIAL AND METHODS
Based on available literature we discuss some important biological properties of glycine and give a short account of our own studies in this field.
RESULTS
The main area of glycine research has traditionally been associated with its role as a neurotransmitter in the central nervous system. During the last few years there has been a mounting interest in effects on other organs and tissues as well. Glycine-gated chloride channels, originally demonstrated on neurons in the central nervous system, have been found on most leukocytes and a number of other cell types. This has provided a unifying mechanism of action that explains how glycine may influence such important and diverse biological processes as transmission of nerve signals and initiation of the immune response.
INTERPRETATION
Glycine is a simple, easily available and inexpensive substance with few and innocuous side effects. Despite the recent unveiling of tantalizing aspects regarding its mechanism of action, biological activities and therapeutic potential, clinical use has remained scant.
Topics: Glycine; Humans; Neurotransmitter Agents; Receptors, Glycine
PubMed: 15039805
DOI: No ID Found -
ACS Chemical Neuroscience Sep 2023The mechanism of the negative impact of corticosteroids on the induction and progress of mental illness remains unclear. In this work, we studied the effects of...
The mechanism of the negative impact of corticosteroids on the induction and progress of mental illness remains unclear. In this work, we studied the effects of corticosteroids on the activity of neuronal glycine receptors (GlyR) and GABA-A receptors (GABAR) by measuring the chloride current induced by the application of GABA (2 or 5 μM) to isolated cerebellar Purkinje cells () and by the application of glycine (100 μM) to pyramidal neurons of the rat hippocampus (). It was found that corticosterone, 5α-dihydrodeoxycorticosterone, allotetrahydrocorticosterone, cortisol, and 17α,21-dihydroxypregnenolone were able to accelerate the desensitization of the at physiological concentrations (IC values varying from 0.39 to 0.72 μM). Next, cortisone, 11-deoxycortisol, 11-deoxycorticosterone, 5β-dihydrodeoxycorticosterone, and tetrahydrocorticosterone accelerated the desensitization of with IC values varying from 10.3 to 15.2 μM. Allotetrahydrocorticosterone and tetrahydrocorticosterone potentiated the albeit with high EC values (18-23 μM). The rest of the steroids had no effect on in the range of concentrations of 1-100 μM. Finally, our study has suggested a structural relationship of the 3β-hydroxyl group/3-oxo group with the selective modulatory activity on GlyRs in contrast to the 3α-hydroxyl group that is pivotal for GABARs. In summary, our results suggest that increased GlyR desensitization by corticosteroids may contribute to brain dysfunction under chronic stress and identify corticosteroids for further development as selective modulators of GlyRs.
Topics: Rats; Animals; Receptors, Glycine; Glycine; Neurons; Receptors, GABA-A; Adrenal Cortex Hormones; gamma-Aminobutyric Acid
PubMed: 37584305
DOI: 10.1021/acschemneuro.3c00287 -
British Journal of Pharmacology Dec 2021Glycine receptors composed of α1 and β subunits are primarily found in the spinal cord and brainstem and are potentiated by ethanol (10-100 mM). However, much less...
BACKGROUND AND PURPOSE
Glycine receptors composed of α1 and β subunits are primarily found in the spinal cord and brainstem and are potentiated by ethanol (10-100 mM). However, much less is known about the presence, composition and ethanol sensitivity of these receptors in higher CNS regions. Here, we examined two regions of the brain reward system, the ventral tegmental area (VTA) and the prefrontal cortex (PFC), to determine their glycine receptor subunit composition and sensitivity to ethanol.
EXPERIMENTAL APPROACH
We used Western blot, immunohistochemistry and electrophysiological techniques in three different models: wild-type C57BL/6, glycine receptor subunit α1 knock-in and glycine receptor subunit α2 knockout mice.
KEY RESULTS
Similar levels of α and β receptor subunits were detected in both brain regions, and electrophysiological recordings demonstrated the presence of glycine-activated currents in both areas. Sensitivity of glycine receptors to glycine was lower in the PFC compared with VTA. Picrotoxin only partly blocked the glycine-activated current in the PFC and VTA, indicating that both regions express heteromeric αβ receptors. Glycine receptors in VTA neurons, but not in PFC neurons, were potentiated by ethanol.
CONCLUSION AND IMPLICATIONS
Glycine receptors in VTA neurons from WT and α2 KO mice were potentiated by ethanol, but not in neurons from the α1 KI mice, supporting the conclusion that α1 glycine receptors are predominantly expressed in the VTA. By contrast, glycine receptors in PFC neurons were not potentiated in any of the mouse models studied, suggesting the presence of α2/α3/α4, rather than α1 glycine receptor subunits.
Topics: Animals; Ethanol; Mice; Mice, Inbred C57BL; Prefrontal Cortex; Receptors, Glycine; Ventral Tegmental Area
PubMed: 34378188
DOI: 10.1111/bph.15649 -
British Journal of Pharmacology Nov 2016Glycine receptors are important players in pain perception and movement disorders and therefore important therapeutic targets. Glycine receptors can be modulated by the...
BACKGROUND AND PURPOSE
Glycine receptors are important players in pain perception and movement disorders and therefore important therapeutic targets. Glycine receptors can be modulated by the intravenous anaesthetic propofol (2,6-diisopropylphenol). However, the drug is more potent, by at least one order of magnitude, on GABA receptors. It has been proposed that halogenation of the propofol molecule generates compounds with selective enhancement of glycinergic modulatory properties.
EXPERIMENTAL APPROACH
We synthesized 4-bromopropofol, 4-chloropropofol and 4-fluoropropofol. The direct activating and modulatory effects of these drugs and propofol were compared on recombinant rat glycine and human GABA receptors expressed in oocytes. Behavioural effects of the compounds were compared in the tadpole loss-of-righting assay.
KEY RESULTS
Concentration-response curves for potentiation of homomeric α1, α2 and α3 glycine receptors were shifted to lower drug concentrations, by 2-10-fold, for the halogenated compounds. Direct activation by all compounds was minimal with all subtypes of the glycine receptor. The four compounds were essentially equally potent modulators of the α1β3γ2L GABA receptor with EC between 4 and 7 μM. The EC for loss-of-righting in Xenopus tadpoles, a proxy for loss of consciousness and considered to be mediated by actions on GABA receptors, ranged from 0.35 to 0.87 μM.
CONCLUSIONS AND IMPLICATIONS
We confirm that halogenation of propofol more strongly affects modulation of homomeric glycine receptors than α1β3γ2L GABA receptors. However, the effective concentrations of all tested halogenated compounds remained lower for GABA receptors. We infer that 4-bromopropofol, 4-chloropropofol and 4-fluoropropofol are not selective homomeric glycine receptor modulators.
Topics: Animals; Dose-Response Relationship, Drug; Humans; Propofol; Rats; Receptors, GABA-A; Receptors, Glycine; Recombinant Proteins; Structure-Activity Relationship; Xenopus laevis
PubMed: 27459129
DOI: 10.1111/bph.13566 -
Biomolecules Nov 2020Reduced inhibitory glycinergic neurotransmission is implicated in a number of neurological conditions such as neuropathic pain, schizophrenia, epilepsy and...
Reduced inhibitory glycinergic neurotransmission is implicated in a number of neurological conditions such as neuropathic pain, schizophrenia, epilepsy and hyperekplexia. Restoring glycinergic signalling may be an effective method of treating these pathologies. Glycine transporters (GlyTs) control synaptic and extra-synaptic glycine concentrations and slowing the reuptake of glycine using specific GlyT inhibitors will increase glycine extracellular concentrations and increase glycine receptor (GlyR) activation. Glycinergic neurotransmission can also be improved through positive allosteric modulation (PAM) of GlyRs. Despite efforts to manipulate this synapse, no therapeutics currently target it. We propose that dual action modulators of both GlyTs and GlyRs may show greater therapeutic potential than those targeting individual proteins. To show this, we have characterized a co-expression system in oocytes consisting of GlyT1 or GlyT2 co-expressed with GlyRα. We use two electrode voltage clamp recording techniques to measure the impact of GlyTs on GlyRs and the effects of modulators of these proteins. We show that increases in GlyT density in close proximity to GlyRs diminish receptor currents. Reductions in GlyR mediated currents are not observed when non-transportable GlyR agonists are applied or when Na is not available. GlyTs reduce glycine concentrations across different concentration ranges, corresponding with their ion-coupling stoichiometry, and full receptor currents can be restored when GlyTs are blocked with selective inhibitors. We show that partial inhibition of GlyT2 and modest GlyRα potentiation using a dual action compound, is as useful in restoring GlyR currents as a full and potent single target GlyT2 inhibitor or single target GlyRα PAM. The co-expression system developed in this study will provide a robust means for assessing the likely impact of GlyR PAMs and GlyT inhibitors on glycine neurotransmission.
Topics: Animals; Biological Assay; Gene Expression; Glycine Plasma Membrane Transport Proteins; Receptors, Glycine; Synapses; Synaptic Transmission; Xenopus laevis
PubMed: 33266066
DOI: 10.3390/biom10121618 -
Physiological Reviews Oct 2004The glycine receptor chloride channel (GlyR) is a member of the nicotinic acetylcholine receptor family of ligand-gated ion channels. Functional receptors of this family... (Review)
Review
The glycine receptor chloride channel (GlyR) is a member of the nicotinic acetylcholine receptor family of ligand-gated ion channels. Functional receptors of this family comprise five subunits and are important targets for neuroactive drugs. The GlyR is best known for mediating inhibitory neurotransmission in the spinal cord and brain stem, although recent evidence suggests it may also have other physiological roles, including excitatory neurotransmission in embryonic neurons. To date, four alpha-subunits (alpha1 to alpha4) and one beta-subunit have been identified. The differential expression of subunits underlies a diversity in GlyR pharmacology. A developmental switch from alpha2 to alpha1beta is completed by around postnatal day 20 in the rat. The beta-subunit is responsible for anchoring GlyRs to the subsynaptic cytoskeleton via the cytoplasmic protein gephyrin. The last few years have seen a surge in interest in these receptors. Consequently, a wealth of information has recently emerged concerning GlyR molecular structure and function. Most of the information has been obtained from homomeric alpha1 GlyRs, with the roles of the other subunits receiving relatively little attention. Heritable mutations to human GlyR genes give rise to a rare neurological disorder, hyperekplexia (or startle disease). Similar syndromes also occur in other species. A rapidly growing list of compounds has been shown to exert potent modulatory effects on this receptor. Since GlyRs are involved in motor reflex circuits of the spinal cord and provide inhibitory synapses onto pain sensory neurons, these agents may provide lead compounds for the development of muscle relaxant and peripheral analgesic drugs.
Topics: Animals; Central Nervous System; Chloride Channels; Humans; Molecular Structure; Neurons; Protein Subunits; Receptors, Glycine
PubMed: 15383648
DOI: 10.1152/physrev.00042.2003 -
Neuron May 2016Nicotinic acetylcholine, serotonin type 3, γ-amminobutyric acid type A, and glycine receptors are major players of human neuronal communication. They belong to the... (Review)
Review
Nicotinic acetylcholine, serotonin type 3, γ-amminobutyric acid type A, and glycine receptors are major players of human neuronal communication. They belong to the family of pentameric ligand-gated ion channels, sharing a highly conserved modular 3D structure. Recently, high-resolution structures of both open- and closed-pore conformations have been solved for a bacterial, an invertebrate, and a vertebrate receptor in this family. These data suggest that a common gating mechanism occurs, coupling neurotransmitter binding to pore opening, but they also pinpoint significant differences among subtypes. In this Review, we summarize the structural and functional data in light of these gating models and speculate about their mechanistic consequences on ion permeation, pathological mutations, as well as functional regulation by orthosteric and allosteric effectors.
Topics: Animals; Biophysical Phenomena; Humans; Ion Channel Gating; Ligand-Gated Ion Channels; Models, Molecular; Receptors, Glycine; Signal Transduction
PubMed: 27151638
DOI: 10.1016/j.neuron.2016.03.032 -
Nature Oct 2015The strychnine-sensitive glycine receptor (GlyR) mediates inhibitory synaptic transmission in the spinal cord and brainstem and is linked to neurological disorders,...
The strychnine-sensitive glycine receptor (GlyR) mediates inhibitory synaptic transmission in the spinal cord and brainstem and is linked to neurological disorders, including autism and hyperekplexia. Understanding of molecular mechanisms and pharmacology of glycine receptors has been hindered by a lack of high-resolution structures. Here we report electron cryo-microscopy structures of the zebrafish α1 GlyR with strychnine, glycine, or glycine and ivermectin (glycine/ivermectin). Strychnine arrests the receptor in an antagonist-bound closed ion channel state, glycine stabilizes the receptor in an agonist-bound open channel state, and the glycine/ivermectin complex adopts a potentially desensitized or partially open state. Relative to the glycine-bound state, strychnine expands the agonist-binding pocket via outward movement of the C loop, promotes rearrangement of the extracellular and transmembrane domain 'wrist' interface, and leads to rotation of the transmembrane domain towards the pore axis, occluding the ion conduction pathway. These structures illuminate the GlyR mechanism and define a rubric to interpret structures of Cys-loop receptors.
Topics: Allosteric Regulation; Animals; Binding Sites; Cryoelectron Microscopy; Glycine; Ion Channel Gating; Ivermectin; Models, Molecular; Neurotransmitter Agents; Protein Conformation; Protein Subunits; Receptors, Glycine; Rotation; Signal Transduction; Strychnine; Zebrafish
PubMed: 26344198
DOI: 10.1038/nature14853 -
The EMBO Journal Aug 2011Glycine receptors (GlyRs) can dynamically exchange between synaptic and extrasynaptic locations through lateral diffusion within the plasma membrane. Their accumulation...
Glycine receptors (GlyRs) can dynamically exchange between synaptic and extrasynaptic locations through lateral diffusion within the plasma membrane. Their accumulation at inhibitory synapses depends on the interaction of the β-subunit of the GlyR with the synaptic scaffold protein gephyrin. An alteration of receptor-gephyrin binding could thus shift the equilibrium between synaptic and extrasynaptic GlyRs and modulate the strength of inhibitory neurotransmission. Using a combination of dynamic imaging and biochemical approaches, we have characterised the molecular mechanism that links the GlyR-gephyrin interaction with GlyR diffusion and synaptic localisation. We have identified a protein kinase C (PKC) phosphorylation site within the cytoplasmic domain of the β-subunit of the GlyR (residue S403) that causes a reduction of the binding affinity between the receptor and gephyrin. In consequence, the receptor's diffusion in the plasma membrane is accelerated and GlyRs accumulate less strongly at synapses. We propose that the regulation of GlyR dynamics by PKC thus contributes to the plasticity of inhibitory synapses and may be involved in maladaptive forms of synaptic plasticity.
Topics: Carrier Proteins; Cell Membrane; Membrane Proteins; Phosphorylation; Protein Binding; Protein Kinase C; Receptors, Glycine
PubMed: 21829170
DOI: 10.1038/emboj.2011.276