Modulators of the Inhibitory Glycine Receptor

Breitinger, Hans‐Georg

doi:10.1021/acschemneuro.0c00054

Cited by 20 publications

(29 citation statements)

References 192 publications

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“…Strychnine-sensitive glycine receptors (GlyRs) are ligand-gated chloride channels mediating fast inhibitory transmission in the spinal cord and brainstem (Breitinger and Breitinger, 2020 ; Zeilhofer et al, 2021 ). These pentameric proteins are composed of α and β subunits.…”

Section: Introductionmentioning

confidence: 99%

Nociception in the Glycine Receptor Deficient Mutant Mouse Spastic

Groemer

Triller

Zeilhofer

et al. 2022

Front. Mol. Neurosci.

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Glycine receptors (GlyRs) are the primary mediators of fast inhibitory transmission in the mammalian spinal cord, where they modulate sensory and motor signaling. Mutations in GlyR genes as well as some other genes underlie the hereditary disorder hyperekplexia, characterized by episodic muscle stiffness and exaggerated startle responses. Here, we have investigated pain-related behavior and GlyR expression in the spinal cord of the GlyR deficient mutant mouse spastic (spa). In spastic mice, the GlyR number is reduced due to a β subunit gene (Glrb) mutation resulting in aberrant splicing of GlyRβ transcripts. Via direct physical interaction with the GlyR anchoring protein gephyrin, this subunit is crucially involved in the postsynaptic clustering of heteromeric GlyRs. We show that the mutation differentially affects aspects of the pain-related behavior of homozygous Glrbspa/Glrbspa mice. While response latencies to noxious heat were unchanged, chemically induced pain-related behavior revealed a reduction of the licking time and an increase in flinching in spastic homozygotes during both phases of the formalin test. Mechanically induced nocifensive behavior was reduced in spastic mice, although hind paw inflammation (by zymosan) resulted in allodynia comparable to wild-type mice. Immunohistochemical staining of the spinal cord revealed a massive reduction of dotted GlyRα subunit immunoreactivity in both ventral and dorsal horns, suggesting a reduction of clustered receptors at synaptic sites. Transcripts for all GlyRα subunit variants, however, were not reduced throughout the dorsal horn of spastic mice. These findings suggest that the loss of functional GlyRβ subunits and hence synaptically localized GlyRs compromises sensory processing differentially, depending on stimulus modality.

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Section: Introductionmentioning

confidence: 99%

Nociception in the Glycine Receptor Deficient Mutant Mouse Spastic

Groemer

Triller

Zeilhofer

et al. 2022

Front. Mol. Neurosci.

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“…Strychnine , a highly toxic alkaloid isolated from the seeds of Strychnos nux‐vomica tree, competitively antagonizes glycine receptors with IC 50 values in the range of 10–50 nM according to radioligand displacement and whole‐cell current measurements. This antagonism can cause convulsions, spastic muscle contractions, and asphyxiation by inhibition GlyRs in the central nervous system of vertebrates, 65 but (−)‐strychnine is commonly used as a pesticide and rodenticide (oral LD 50 = 16 mg kg −1 in rats, 2 mg kg −1 in mice). A high‐resolution (3.0 Å) crystal structure of strychnine in complex with human a GlyRα3 homopentamer revealed a mechanism for antagonist‐induced inactivation of GlyRs and reflected its unique orthosteric binding site on the extracellular domain 66 .…”

Section: Glyr Antagonistsmentioning

confidence: 99%

Change the channel: CysLoop receptor antagonists from nature

Tong

Baker

Shenvi

2020

Pest Management Science

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Vertebrate and invertebrate ligand‐gated ion channels (LGICs) exhibit significant structural homology and often share ligands. As a result, ligands with activity against one class can be brought to bear against another, including for development as insecticides. Receptor selectivity, metabolism and distribution must then be optimized using chemical synthesis. Here we review natural products (NPs) that ligate and inhibit the Cys‐loop family of LGICs, which benefit from the unique physicochemical properties of natural product space but often present a high synthetic burden. Recent advances in chemical synthesis, however, have opened practical entries into these complex structures, several of which are highlighted. © 2020 Society of Chemical Industry

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“…In mammalian organisms, the superfamily of pentameric ligand gated ion channels (pLGICs, also often termed cys-loop receptors) comprises ligand gated cation and anion channels, many of which are highly expressed in the mammalian nervous system. Several members of the superfamily are well established targets of important neuropsychiatric medications ( Young and Snyder, 1973 ; Walstab et al, 2010 ; Dineley et al, 2015 ; Sieghart and Savic, 2018 ; Tregellas and Wylie, 2019 ; Breitinger and Breitinger, 2020 ; Caton et al, 2020 ). Beyond clinically approved drugs, several pLGICs are also targets of recreational and illicit drugs, and mediate toxicological effects by many synthetic, plant- and animal derived toxins ( Ho and Flood, 2004 ; Johnston et al, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

“…A pharmacological distinction between GABA A Rs and GlyRs can be made with the highly specific orthosteric antagonist strychnine, a plant derived toxin. Pathophysiologically, strychnine-induced convulsions occur at low doses due to the block of GlyR-mediated inhibition, whereas GABA A Rs are blocked at much higher concentrations ( Breitinger and Breitinger, 2020 ). Additionally, tranexamic acid and ε-aminocaproic acid are two clinically used antifibrinolytics which can cause convulsions as a GlyR-mediated side effect ( Lecker et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, tranexamic acid and ε-aminocaproic acid are two clinically used antifibrinolytics which can cause convulsions as a GlyR-mediated side effect ( Lecker et al, 2012 ). The GlyRs high promiscuity within the pLGIC family is reflected by the number and diversity of compounds that bind to and modulate the receptors, such as taurine, beta-alanine, ivermectin, bicuculline, gabazine, as well as fluoxetine and clozapine ( Breitinger and Breitinger, 2020 ). Many more clinically used therapeutics modulate GlyRs and might elicit some fraction of their adverse effects via unwanted modulation of these receptors, especially at higher dosages.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Mingling: Multimodal Predictions of Ligand Promiscuity in Pentameric Ligand-Gated Ion Channels

Koniuszewski

Vogel

Bampali

et al. 2022

Front. Mol. Biosci.

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Background: Human pentameric ligand-gated ion channels (pLGICs) comprise nicotinic acetylcholine receptors (nAChRs), 5-hydroxytryptamine type 3 receptors (5-HT3Rs), zinc-activated channels (ZAC), γ-aminobutyric acid type A receptors (GABAARs) and glycine receptors (GlyRs). They are recognized therapeutic targets of some of the most prescribed drugs like general anesthetics, anxiolytics, smoking cessation aids, antiemetics and many more. Currently, approximately 100 experimental structures of pLGICs with ligands bound exist in the protein data bank (PDB). These atomic-level 3D structures enable the generation of a comprehensive binding site inventory for the superfamily and the in silico prediction of binding site properties.Methods: A panel of high throughput in silico methods including pharmacophore screening, conformation analysis and descriptor calculation was applied to a selection of allosteric binding sites for which in vitro screens are lacking. Variant abundance near binding site forming regions and computational docking complement the approach.Results: The structural data reflects known and novel binding sites, some of which may be unique to individual receptors, while others are broadly conserved. The membrane spanning domain, comprising four highly conserved segments, contains ligand interaction sites for which in vitro assays suitable for high throughput screenings are critically lacking. This is also the case for structurally more variable novel sites in the extracellular domain. Our computational results suggest that the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) can utilize multiple pockets which are likely to exist on most superfamily members.Conclusion: With this study, we explore the potential for polypharmacology among pLGICs. Our data suggest that ligands can display two forms of promiscuity to an extent greater than what has been realized: 1) Ligands can interact with homologous sites in many members of the superfamily, which bears toxicological relevance. 2) Multiple pockets in distinct localizations of individual receptor subtypes share common ligands, which counteracts efforts to develop selective agents. Moreover, conformational states need to be considered for in silico drug screening, as certain binding sites display considerable flexibility. In total, this work contributes to a better understanding of polypharmacology across pLGICs and provides a basis for improved structure guided in silico drug development and drug derisking.

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Modulators of the Inhibitory Glycine Receptor

Cited by 20 publications

References 192 publications

Nociception in the Glycine Receptor Deficient Mutant Mouse Spastic

Nociception in the Glycine Receptor Deficient Mutant Mouse Spastic

Change the channel: CysLoop receptor antagonists from nature

Molecular Mingling: Multimodal Predictions of Ligand Promiscuity in Pentameric Ligand-Gated Ion Channels

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