{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T02:19:47Z","timestamp":1790129987303,"version":"4.0.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T00:00:00Z","timestamp":1660003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Glycine receptors (GlyRs) are pentameric ion channels that mediate fast inhibitory neurotransmission. GlyRs are found in the central nervous system including the spinal cord, brain stem, and cerebellum, as well as in the retina, sperm, macrophages, hippocampus, cochlea, and liver. Due to their crucial roles in counter-balancing excitatory signals and pain signal transmission, GlyR dysfunction can lead to severe diseases, and as a result, compounds that modify GlyR activity may have tremendous therapeutic potential. Despite this potential, the development of GlyR-specific small-molecule ligands is lacking. Over the past few years, high-resolution structures of both homomeric and heteromeric GlyRs structures in various conformations have provided unprecedented details defining the pharmacology of ligand binding, subunit composition, and mechanisms of channel gating. These high-quality structures will undoubtedly help with the development of GlyR-targeted therapies.<\/jats:p>","DOI":"10.3389\/fphar.2022.925116","type":"journal-article","created":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T05:50:11Z","timestamp":1660024211000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Structure and Mechanism of Glycine Receptor Elucidated by Cryo-Electron Microscopy"],"prefix":"10.3389","volume":"13","author":[{"given":"Hongtao","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/0014-5793(91)80383-e","article-title":"Cloning of a glycine Receptor Subtype Expressed in Rat Brain and Spinal Cord during a Specific Period of Neuronal Development","volume":"281","author":"Akagi","year":"1991","journal-title":"FEBS Lett."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3717","DOI":"10.1002\/j.1460-2075.1988.tb03255.x","article-title":"Glycine Receptor Heterogeneity in Rat Spinal Cord during Postnatal Development","volume":"7","author":"Becker","year":"1988","journal-title":"EMBO J."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1706","DOI":"10.1021\/acschemneuro.0c00054","article-title":"Modulators of the Inhibitory Glycine Receptor","volume":"11","author":"Breitinger","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"353","DOI":"10.3109\/714041016","article-title":"Stoichiometry of Recombinant Heteromeric glycine Receptors Revealed by a Pore-Lining Region Point Mutation","volume":"9","author":"Burzomato","year":"2003","journal-title":"Recept Channels"},{"key":"B5","volume-title":"Principles and Practice of Pharmacology for Anaesthetists","author":"Calvey","year":"2008"},{"key":"B6","doi-asserted-by":"publisher","first-page":"3379","DOI":"10.1093\/bioinformatics\/btaa170","article-title":"The Glycine Receptor Allosteric Ligands Library (GRALL)","volume":"36","author":"Cerdan","year":"2020","journal-title":"Bioinformatics"},{"key":"B7","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1016\/s0028-3908(99)00015-5","article-title":"Functional Integrity of Green Fluorescent Protein Conjugated glycine Receptor Channels","volume":"38","author":"David-Watine","year":"1999","journal-title":"Neuropharmacology"},{"key":"B8","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1111\/j.1469-7793.2001.t01-1-00741.x","article-title":"Activation of Human Alpha1 and Alpha2 Homomeric glycine Receptors by Taurine and GABA","volume":"535","author":"De Saint Jan","year":"2001","journal-title":"J. Physiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1038\/nature14853","article-title":"Glycine Receptor Mechanism Elucidated by Electron Cryo-Microscopy","volume":"526","author":"Du","year":"2015","journal-title":"Nature"},{"key":"B10","doi-asserted-by":"publisher","first-page":"12915","DOI":"10.1523\/JNEUROSCI.2050-12.2012","article-title":"Stoichiometry of the Human glycine Receptor Revealed by Direct Subunit Counting","volume":"32","author":"Durisic","year":"2012","journal-title":"J. Neurosci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"40216","DOI":"10.1074\/jbc.R112.408229","article-title":"Inhibitory glycine Receptors: an Update","volume":"287","author":"Dutertre","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1085\/jgp.201711803","article-title":"Chasing the Open-State Structure of Pentameric Ligand-Gated Ion Channels","volume":"149","author":"Gonzalez-Gutierrez","year":"2017","journal-title":"J. Gen. Physiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1021\/bi00325a027","article-title":"Purification and Characterization of the glycine Receptor of Pig Spinal Cord","volume":"24","author":"Graham","year":"1985","journal-title":"Biochemistry"},{"key":"B14","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/0092-8674(93)90294-z","article-title":"Acetylcholine Receptor Assembly: Subunit Folding and Oligomerization Occur Sequentially","volume":"74","author":"Green","year":"1993","journal-title":"Cell."},{"key":"B15","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/328215a0","article-title":"The Strychnine-Binding Subunit of the glycine Receptor Shows Homology with Nicotinic Acetylcholine Receptors","volume":"328","author":"Grenningloh","year":"1987","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1016\/0896-6273(90)90149-a","article-title":"Cloning and Expression of the 58 Kd Beta Subunit of the Inhibitory glycine Receptor","volume":"4","author":"Grenningloh","year":"1990","journal-title":"Neuron"},{"key":"B17","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/j.neuron.2005.01.028","article-title":"The Beta Subunit Determines the Ligand Binding Properties of Synaptic glycine Receptors","volume":"45","author":"Grudzinska","year":"2005","journal-title":"Neuron"},{"key":"B18","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1038\/nature14972","article-title":"Crystal Structure of Human glycine Receptor-\u03913 Bound to Antagonist Strychnine","volume":"526","author":"Huang","year":"2015","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1016\/j.str.2017.04.007","article-title":"Crystal Structures of Human GlyR\u03b13 Bound to Ivermectin","volume":"25","author":"Huang","year":"","journal-title":"Structure"},{"key":"B20","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1038\/nsmb.3329","article-title":"Crystal Structures of Human glycine Receptor \u03b13 Bound to a Novel Class of Analgesic Potentiators","volume":"24","author":"Huang","year":"","journal-title":"Nat. Struct. Mol. Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"280","DOI":"10.3389\/fnmol.2019.00280","article-title":"Modulation of Glycine Receptor-Mediated Pain Signaling In Vitro and In Vivo by Glucose","volume":"12","author":"Hussein","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1126\/science.281.5375.419","article-title":"Corelease of Two Fast Neurotransmitters at a Central Synapse","volume":"281","author":"Jonas","year":"1998","journal-title":"Science"},{"key":"B23","doi-asserted-by":"publisher","first-page":"16024","DOI":"10.1074\/jbc.M009508200","article-title":"Detection and Binding Properties of GABA(A) Receptor Assembly Intermediates","volume":"276","author":"Klausberger","year":"2001","journal-title":"J. Biol. Chem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/0014-5793(91)80557-j","article-title":"Alternative Splicing Generates Two Isoforms of the Alpha 2 Subunit of the Inhibitory glycine Receptor","volume":"283","author":"Kuhse","year":"1991","journal-title":"FEBS Lett."},{"key":"B25","doi-asserted-by":"publisher","first-page":"3752","DOI":"10.1038\/s41467-020-17364-5","article-title":"Mechanisms of Activation and Desensitization of Full-Length glycine Receptor in Lipid Nanodiscs","volume":"11","author":"Kumar","year":"2020","journal-title":"Nat. Commun."},{"key":"B26","doi-asserted-by":"publisher","first-page":"7394","DOI":"10.1073\/pnas.85.19.7394","article-title":"Conserved Quaternary Structure of Ligand-Gated Ion Channels: the Postsynaptic glycine Receptor Is a Pentamer","volume":"85","author":"Langosch","year":"1988","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B27","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1038\/nature07139","article-title":"On the Nature of Partial Agonism in the Nicotinic Receptor Superfamily","volume":"454","author":"Lape","year":"2008","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1336","DOI":"10.1523\/JNEUROSCI.4346-11.2012","article-title":"The \u03b11K276E Startle Disease Mutation Reveals Multiple Intermediate States in the Gating of glycine Receptors","volume":"32","author":"Lape","year":"2012","journal-title":"J. Neurosci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1007\/pl00000899","article-title":"The Glycinergic Inhibitory Synapse","volume":"58","author":"Legendre","year":"2001","journal-title":"Cell. Mol. Life Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.tins.2004.04.002","article-title":"Cys-loop Receptors: New Twists and Turns","volume":"27","author":"Lester","year":"2004","journal-title":"Trends Neurosci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1152\/physrev.00042.2003","article-title":"Molecular Structure and Function of the glycine Receptor Chloride Channel","volume":"84","author":"Lynch","year":"2004","journal-title":"Physiol. Rev."},{"key":"B32","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/j.neuropharm.2008.07.034","article-title":"Native glycine Receptor Subtypes and Their Physiological Roles","volume":"56","author":"Lynch","year":"2009","journal-title":"Neuropharmacology"},{"key":"B33","doi-asserted-by":"publisher","first-page":"2607","DOI":"10.1016\/s0021-9258(17)41987-9","article-title":"Structural Analysis of Mouse glycine Receptor Alpha Subunit Genes. Identification and Chromosomal Localization of a Novel Variant","volume":"269","author":"Matzenbach","year":"1994","journal-title":"J. Biol. Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"9389","DOI":"10.1016\/s0021-9258(18)34082-1","article-title":"Purification by Affinity Chromatography of the glycine Receptor of Rat Spinal Cord","volume":"257","author":"Pfeiffer","year":"1982","journal-title":"J. Biol. Chem."},{"key":"B35","doi-asserted-by":"publisher","first-page":"4305","DOI":"10.1002\/j.1460-2075.1992.tb05529.x","article-title":"The Atypical M2 Segment of the Beta Subunit Confers Picrotoxinin Resistance to Inhibitory glycine Receptor Channels","volume":"11","author":"Pribilla","year":"1992","journal-title":"EMBO J."},{"key":"B36","doi-asserted-by":"publisher","first-page":"12556","DOI":"10.1074\/jbc.M011264200","article-title":"Ivermectin, an Unconventional Agonist of the glycine Receptor Chloride Channel","volume":"276","author":"Shan","year":"","journal-title":"J. Biol. Chem."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1046\/j.1471-4159.2001.00124.x","article-title":"A Single Beta Subunit M2 Domain Residue Controls the Picrotoxin Sensitivity of Alphabeta Heteromeric glycine Receptor Chloride Channels","volume":"76","author":"Shan","year":"","journal-title":"J. Neurochem."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3841","DOI":"10.1074\/jbc.M511022200","article-title":"Mechanisms for Picrotoxin Block of Alpha2 Homomeric glycine Receptors","volume":"281","author":"Wang","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B39","doi-asserted-by":"publisher","first-page":"5229","DOI":"10.1021\/bi300063m","article-title":"Stoichiometry and Subunit Arrangement of \u03b11\u03b2 glycine Receptors as Determined by Atomic Force Microscopy","volume":"51","author":"Yang","year":"2012","journal-title":"Biochemistry"},{"key":"B40","doi-asserted-by":"publisher","first-page":"2707","DOI":"10.1016\/j.neuron.2021.08.019","article-title":"Characterization of the Subunit Composition and Structure of Adult Human glycine Receptors","volume":"109","author":"Yu","year":"","journal-title":"Neuron"},{"key":"B41","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1016\/j.cell.2021.01.026","article-title":"Mechanism of Gating and Partial Agonist Action in the glycine Receptor","volume":"184","author":"Yu","year":"","journal-title":"Cell."},{"key":"B42","doi-asserted-by":"publisher","first-page":"846","DOI":"10.3390\/biom11060846","article-title":"Glycine Receptors in Spinal Nociceptive Control-An Update","volume":"11","author":"Zeilhofer","year":"2021","journal-title":"Biomolecules"},{"key":"B43","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/s41586-021-04022-z","article-title":"Architecture and Assembly Mechanism of Native glycine Receptors","volume":"599","author":"Zhu","year":"2021","journal-title":"Nature"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.925116\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T05:50:14Z","timestamp":1660024214000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.925116\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,9]]},"references-count":43,"alternative-id":["10.3389\/fphar.2022.925116"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.925116","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,9]]},"article-number":"925116"}}