{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T03:58:59Z","timestamp":1793332739156,"version":"4.5.0"},"reference-count":123,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T00:00:00Z","timestamp":1669766400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Neuroscience Startup, University of Texas at Austin","id":[{"id":"https:\/\/ror.org\/00hj54h04","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Benzodiazepines (BZDs) are a class of widely prescribed psychotropic drugs that target GABAA receptors (GABAARs) to tune inhibitory synaptic signaling throughout the central nervous system. Despite knowing their molecular target for over 40 years, we still do not fully understand the mechanism of modulation at the level of the channel protein. Nonetheless, functional studies, together with recent cryo-EM structures of GABAA(\u03b11)2(\u03b2X)2(\u03b32)1 receptors in complex with BZDs, provide a wealth of information to aid in addressing this gap in knowledge. Here, mechanistic interpretations of functional and structural evidence for the action of BZDs at GABAA(\u03b11)2(\u03b2X)2(\u03b32)1 receptors are reviewed. The goal is not to describe each of the many studies that are relevant to this discussion nor to dissect in detail all the effects of individual mutations or perturbations but rather to highlight general mechanistic principles in the context of recent structural information.<\/jats:p>","DOI":"10.3390\/biom12121784","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T02:21:57Z","timestamp":1669774917000},"page":"1784","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":123,"title":["Benzodiazepine Modulation of GABAA Receptors: A Mechanistic Perspective"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1466-9808","authenticated-orcid":false,"given":"Marcel P.","family":"Goldschen-Ohm","sequence":"first","affiliation":[{"name":"Department of Neuroscience, University of Texas at Austin, Austin, TX 78712, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e2131012","DOI":"10.1001\/jamanetworkopen.2021.31012","article-title":"Trends in the Use of Benzodiazepines, Z-Hypnotics, and Serotonergic Drugs Among US Women and Men Before and During the COVID-19 Pandemic","volume":"4","author":"Milani","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1124\/jpet.300.1.2","article-title":"A New Benzodiazepine Pharmacology","volume":"300","author":"Fritschy","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1177\/2045125317753340","article-title":"Challenges of the pharmacological management of benzodiazepine withdrawal, dependence, and discontinuation","volume":"8","author":"Fluyau","year":"2018","journal-title":"Ther. Adv. Psychopharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"120","DOI":"10.9740\/mhc.2016.05.120","article-title":"Benzodiazepine Use, Misuse, and Abuse: A Review","volume":"6","author":"Schmitz","year":"2016","journal-title":"Ment. Health Clin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.amepre.2015.03.040","article-title":"Emergency Department Visits and Overdose Deaths from Combined Use of Opioids and Benzodiazepines","volume":"49","author":"Jones","year":"2015","journal-title":"Am. J. Prev. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1177\/0897190013515001","article-title":"Benzodiazepines: A major component in unintentional prescription drug overdoses with opioid analgesics","volume":"27","author":"Jann","year":"2014","journal-title":"J. Pharm. Pr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2398212819858249","DOI":"10.1177\/2398212819858249","article-title":"A half century of \u03b3-aminobutyric acid","volume":"3","author":"Smart","year":"2019","journal-title":"Brain Neurosci. Adv."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.neuropharm.2018.01.036","article-title":"GABAA receptor: Positive and negative allosteric modulators","volume":"136","author":"Olsen","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1113\/jphysiol.2007.143602","article-title":"GABA transient sets the susceptibility of mIPSCs to modulation by benzodiazepine receptor agonists in rat hippocampal neurons","volume":"585","author":"Mozrzymas","year":"2007","journal-title":"J. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9898","DOI":"10.1523\/JNEUROSCI.5883-09.2010","article-title":"Slow GABA Transient and Receptor Desensitization Shape Synaptic Responses Evoked by Hippocampal Neurogliaform Cells","volume":"30","author":"Karayannis","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1021\/jm00187a001","article-title":"The benzodiazepine story","volume":"22","author":"Sternbach","year":"1979","journal-title":"J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"616298","DOI":"10.3389\/fnins.2020.616298","article-title":"Looking for Novelty in an \u201cOld\u201d Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology","volume":"14","author":"Castellano","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"538","DOI":"10.4140\/TCP.n.2013.538","article-title":"The History of Benzodiazepines","volume":"28","author":"Wick","year":"2013","journal-title":"Consult. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1126\/science.918669","article-title":"Benzodiazepine Receptor: Demonstration in the Central Nervous System","volume":"198","author":"Okada","year":"1977","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.1016\/0024-3205(77)90191-6","article-title":"Properties of 3H-diazepam binding to benzodiazepine receptors in rat cerebral cortex","volume":"20","author":"Okada","year":"1977","journal-title":"Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3805","DOI":"10.1073\/pnas.74.9.3805","article-title":"Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam binding","volume":"74","author":"Braestrup","year":"1977","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/269702a0","article-title":"High densities of benzodiazepine receptors in human cortical areas","volume":"269","author":"Braestrup","year":"1977","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1471-4159.1981.tb05284.x","article-title":"GABA-Benzodiazepine-Barbiturate Receptor Interactions","volume":"37","author":"Olsen","year":"1981","journal-title":"J. Neurochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/0014-5793(82)81008-9","article-title":"Isolation of a GABA receptor from bovine brain using a benzodiazepine affinity column","volume":"147","author":"Sigel","year":"1982","journal-title":"FEBS Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6965","DOI":"10.1016\/S0021-9258(18)32319-6","article-title":"A gamma-aminobutyric acid\/benzodiazepine receptor complex of bovine cerebral cortex","volume":"258","author":"Sigel","year":"1983","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7219","DOI":"10.1016\/S0021-9258(17)39860-5","article-title":"A gamma-aminobutyric acid\/benzodiazepine receptor complex from bovine cerebral cortex. Improved purification with preservation of regulatory sites and their interactions","volume":"259","author":"Sigel","year":"1984","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4837","DOI":"10.1073\/pnas.82.14.4837","article-title":"Monoclonal antibodies reveal structural homogeneity of gamma-aminobutyric acid\/benzodiazepine receptors in different brain areas","volume":"82","author":"Schoch","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1002\/j.1460-2075.1987.tb04791.x","article-title":"The GABAA\/benzodiazepine receptor is a heterotetramer of homologous alpha and beta subunits","volume":"6","author":"Mamalaki","year":"1987","journal-title":"EMBO J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/328221a0","article-title":"Sequence and functional expression of the GABAA receptor shows a ligand-gated receptor super-family","volume":"328","author":"Schofield","year":"1987","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/978-1-4757-5971-6_3","article-title":"Molecular Biology of the GABAA Receptor","volume":"236","author":"Barnard","year":"1988","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1101\/SQB.1990.055.01.006","article-title":"The GABAA Receptor Family: Molecular and Functional Diversity","volume":"55","author":"Seeburg","year":"1990","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1038\/338582a0","article-title":"Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology","volume":"338","author":"Pritchett","year":"1989","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1124\/pr.108.00505","article-title":"International Union of Pharmacology. LXX. Subtypes of \u03b3-Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Composition, Pharmacology, and Function. Update","volume":"60","author":"Olsen","year":"2008","journal-title":"Pharmacol. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1038\/44579","article-title":"Benzodiazepine actions mediated by specific \u03b3-aminobutyric acidA receptor subtypes","volume":"401","author":"Rudolph","year":"1999","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1126\/science.290.5489.131","article-title":"Molecular and Neuronal Substrate for the Selective Attenuation of Anxiety","volume":"290","author":"Crestani","year":"2000","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/75761","article-title":"Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor \u03b11 subtype","volume":"3","author":"McKernan","year":"2000","journal-title":"Nat. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/S0165-6147(00)01773-9","article-title":"Anxiolytic-like action of diazepam: Which GABAA receptor subtype is involved?","volume":"22","author":"Reynolds","year":"2001","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1073\/pnas.0405621102","article-title":"Different GABA A receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates","volume":"102","author":"Rowlett","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e00433","DOI":"10.1002\/prp2.433","article-title":"The role of loops B and C in determining the potentiation of GABA A receptors by midazolam","volume":"6","author":"Moody","year":"2018","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1038\/nn.4102","article-title":"Regulating anxiety with extrasynaptic inhibition","volume":"18","author":"Botta","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1038\/npp.2016.49","article-title":"A Pharmacogenetic \u2018Restriction-of-Function\u2019 Approach Reveals Evidence for Anxiolytic-Like Actions Mediated by \u03b15-Containing GABAA Receptors in Mice","volume":"41","author":"Behlke","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.tins.2011.01.004","article-title":"Hooked on benzodiazepines: GABAA receptor subtypes and addiction","volume":"34","author":"Tan","year":"2011","journal-title":"Trends Neurosci."},{"key":"ref_38","first-page":"1253","article-title":"Pharmacological modulation of the diazepam-insensitive recombinant gamma-aminobutyric acidA receptors alpha 4 beta 2 gamma 2 and alpha 6 beta 2 gamma 2","volume":"50","author":"Knoflach","year":"1996","journal-title":"Mol. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/nrn1625","article-title":"Variations on an inhibitory theme: Phasic and tonic activation of GABAA receptors","volume":"6","author":"Farrant","year":"2005","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7769","DOI":"10.1073\/pnas.0400220101","article-title":"Positioning of the \u03b1-subunit isoforms confers a functional signature to \u03b3-aminobutyric acid type A receptors","volume":"101","author":"Minier","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1124\/pr.117.014449","article-title":"International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans","volume":"70","author":"Sieghart","year":"2018","journal-title":"Pharmacol. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/s41586-018-0255-3","article-title":"Structure of a human synaptic GABAA receptor","volume":"559","author":"Zhu","year":"2018","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"39383","DOI":"10.7554\/eLife.39383","article-title":"Cryo-EM structure of the benzodiazepine-sensitive \u03b11\u03b21\u03b32S tri-heteromeric GABAA receptor in complex with GABA","volume":"7","author":"Phulera","year":"2018","journal-title":"eLife"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/s41586-018-0833-4","article-title":"Cryo-EM structure of the human \u03b11\u03b23\u03b32 GABAA receptor in a lipid bilayer","volume":"565","author":"Laverty","year":"2019","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/s41586-018-0832-5","article-title":"GABAA receptor signalling mechanisms revealed by structural pharmacology","volume":"565","author":"Masiulis","year":"2019","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/s41586-020-2654-5","article-title":"Shared structural mechanisms of general anaesthetics and benzodiazepines","volume":"585","author":"Kim","year":"2020","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/s41586-022-04517-3","article-title":"Differential assembly diversifies GABAA receptor structures and signalling","volume":"604","author":"Sente","year":"2022","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4582","DOI":"10.1038\/s41467-022-32212-4","article-title":"Structural and dynamic mechanisms of GABAA receptor modulators with opposing activities","volume":"13","author":"Zhu","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"795","DOI":"10.2174\/1568026023393507","article-title":"Subunit Composition, Distribution and Function of GABA-A Receptor Subtypes","volume":"2","author":"Sieghart","year":"2002","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1016\/S0021-9258(18)45961-3","article-title":"A single histidine in GABAA receptors is essential for benzodiazepine agonist binding","volume":"267","author":"Wieland","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/S0014-5793(98)00803-5","article-title":"Pharmacology of recombinant \u03b3-aminobutyric acidA receptors rendered diazepam-insensitive by point-mutated \u03b1-subunits","volume":"431","author":"Benson","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1146\/annurev.pharmtox.44.101802.121429","article-title":"Analysis of GABAA Receptor Function and Dissection of the Pharmacology of Benzodiazepines and General Anesthetics Through Mouse Genetics","volume":"44","author":"Rudolph","year":"2004","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1124\/mol.51.5.833","article-title":"Two Tyrosine Residues on the \u03b1 Subunit Are Crucial for Benzodiazepine Binding and Allosteric Modulation of \u03b3-Aminobutyric AcidA Receptors","volume":"51","author":"Amin","year":"1997","journal-title":"Mol. Pharmacol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1124\/mol.54.1.33","article-title":"Photoaffinity Labeling of the Benzodiazepine Binding Site of \u03b11\u03b23\u03b32 \u03b3-Aminobutyric AcidA Receptors with Flunitrazepam Identifies a Subset of Ligands that Interact Directly with His102 of the \u03b1 Subunit and Predicts Orientation of These within the Benzodiazepine Pharmacophore","volume":"54","author":"McKernan","year":"1998","journal-title":"Mol. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"241","DOI":"10.2174\/156802611794863562","article-title":"A Closer Look at the High Affinity Benzodiazepine Binding Site on GABAA Receptors","volume":"11","author":"Sigel","year":"2011","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/S0165-6147(00)01674-6","article-title":"Cysteine mutants as chemical sensors for ligand\u2013receptor interactions","volume":"22","author":"Foucaud","year":"2001","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1124\/mol.110.069542","article-title":"Different Residues in the GABAA Receptor Benzodiazepine Binding Pocket Mediate Benzodiazepine Efficacy and Binding","volume":"80","author":"Morlock","year":"2011","journal-title":"Mol. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1124\/mol.52.5.874","article-title":"Key Amino Acids in the \u03b3 Subunit of the \u03b3-Aminobutyric AcidA Receptor that Determine Ligand Binding and Modulation at the Benzodiazepine Site","volume":"52","author":"Wingrove","year":"1997","journal-title":"Mol. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.1021\/cb500186a","article-title":"Relative Positioning of Classical Benzodiazepines to the \u03b32-Subunit of GABAA Receptors","volume":"9","author":"Middendorp","year":"2014","journal-title":"ACS Chem. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1124\/mol.106.029595","article-title":"Structural Determinants for High-Affinity Zolpidem Binding to GABA-A receptors","volume":"71","author":"Sancar","year":"2006","journal-title":"Mol. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1038\/81800","article-title":"Benzodiazepines act on GABAA receptors via two distinct and separable mechanisms","volume":"3","author":"Walters","year":"2000","journal-title":"Nat. Neurosci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1124\/mol.118.115048","article-title":"Monod-Wyman-Changeux Allosteric Shift Analysis in Mutant \u03b11\u03b23\u03b32L GABAA Receptors Indicates Selectivity and Crosstalk among Intersubunit Transmembrane Anesthetic Sites","volume":"95","author":"Szabo","year":"2019","journal-title":"Mol. Pharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4842","DOI":"10.1111\/bph.15662","article-title":"Selective actions of benzodiazepines at the transmembrane anaesthetic binding sites of the GABAA receptor: In vitro and in vivo studies","volume":"178","author":"McGrath","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"117033","DOI":"10.1016\/j.lfs.2019.117033","article-title":"Flumazenil-insensitive benzodiazepine binding sites in GABAA receptors contribute to benzodiazepine-induced immobility in zebrafish larvae","volume":"239","author":"Cao","year":"2019","journal-title":"Life Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1111\/j.1471-4159.2008.05574.x","article-title":"Covalent modification of GABAA receptor isoforms by a diazepam analogue provides evidence for a novel benzodiazepine binding site that prevents modulation by these drugs","volume":"106","author":"Baur","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"15498","DOI":"10.1038\/s41598-017-15628-7","article-title":"\u03b1 subunits in GABAA receptors are dispensable for GABA and diazepam action","volume":"7","author":"Wongsamitkul","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1523\/JNEUROSCI.5012-10.2011","article-title":"The GABAA receptor \u03b1+\u03b2- interface: A novel target for subtype selective drugs","volume":"31","author":"Ramerstorfer","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.tips.2018.03.006","article-title":"The Benzodiazepine Binding Sites of GABAA Receptors","volume":"39","author":"Sigel","year":"2018","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Lian, J.-J., Cao, Y.-Q., Li, Y.-L., Yu, G., and Su, R.-B. (2020). Flumazenil-Insensitive Benzodiazepine Effects in Recombinant \u03b1\u03b2 and Neuronal GABAA Receptors. Brain Sci., 10.","DOI":"10.3390\/brainsci10030150"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/ana.410250302","article-title":"Differential regulation of \u03b3-aminobutyric acid receptor channels by diazepam and phenobarbital","volume":"25","author":"Twyman","year":"1989","journal-title":"Ann. Neurol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1016\/S0028-3908(96)00077-9","article-title":"Direct Evidence For Diazepam Modulation of GABAA Receptor Microscopic Affinity","volume":"35","author":"Lavoie","year":"1996","journal-title":"Neuropharmacology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1113\/jphysiol.1994.sp020050","article-title":"Benzodiazepine and beta-carboline regulation of single GABAA receptor channels of mouse spinal neurones in culture","volume":"475","author":"Rogers","year":"1994","journal-title":"J. Physiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1523\/JNEUROSCI.19-02-00578.1999","article-title":"Effect of zolpidem on miniature IPSCs and occupancy of postsynaptic GABAA receptors in central synapses","volume":"19","author":"Perrais","year":"1999","journal-title":"J. Neurosci."},{"key":"ref_74","first-page":"1195","article-title":"Actions of benzodiazepine and beta-carboline derivatives on gamma-aminobutyric acid-activated Cl- channels recorded from membrane patches of neonatal rat cortical neurons in culture","volume":"243","author":"Vicini","year":"1987","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1097\/ALN.0b013e318289bcd3","article-title":"The Benzodiazepine Diazepam Potentiates Responses of \u03b11\u03b22\u03b32L \u03b3-Aminobutyric Acid Type A Receptors Activated by either \u03b3-Aminobutyric Acid or Allosteric Agonists","volume":"118","author":"Li","year":"2013","journal-title":"Anesthesiology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/274383a0","article-title":"GABAergic modulation of benzodiazepine binding site sensitivity","volume":"274","author":"Tallman","year":"1978","journal-title":"Nature"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1073\/pnas.76.2.1004","article-title":"Stimulation of benzodiazepine receptor binding by gamma-aminobutyric acid","volume":"76","author":"Karobath","year":"1979","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1124\/mol.108.044891","article-title":"Individually Monitoring Ligand-Induced Changes in the Structure of the GABAA Receptor at Benzodiazepine Binding Site and Non-Binding-Site Interfaces","volume":"74","author":"Sharkey","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.neuropharm.2010.11.009","article-title":"Allosteric modulators induce distinct movements at the GABA-binding site interface of the GABA-A receptor","volume":"60","author":"Sancar","year":"2011","journal-title":"Neuropharmacology"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e202213177","DOI":"10.1085\/jgp.202213177","article-title":"The surprising difficulty of \u201csimple\u201d equilibrium binding measurements on ligand-gated ion channels","volume":"154","author":"Middendorf","year":"2022","journal-title":"J. Gen. Physiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1085\/jgp.201611702","article-title":"Structural identifiability of equilibrium ligand-binding parameters","volume":"149","author":"Middendorf","year":"2016","journal-title":"J. Gen. Physiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1111\/j.1469-7793.1997.353bh.x","article-title":"Frequency-Dependent Actions of Benzodiazepines on GABAA Receptors in Cultured Murine Cerebellar Granule Cells","volume":"503","author":"Mellor","year":"1997","journal-title":"J. Physiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1097\/WNR.0b013e3280c1e2fb","article-title":"Benzodiazepine receptor agonists affect both binding and gating of recombinant \u03b11\u03b22\u03b32 gamma-aminobutyric acid-A receptors","volume":"18","author":"Mercik","year":"2007","journal-title":"NeuroReport"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1097\/00000542-200504000-00014","article-title":"Classic Benzodiazepines Modulate the Open\u2013Close Equilibrium in \u03b11\u03b22\u03b32L\u03b3-Aminobutyric Acid Type A Receptors","volume":"102","author":"Forman","year":"2005","journal-title":"Anesthesiology"},{"key":"ref_85","first-page":"984","article-title":"Mechanism of action of benzodiazepines on GABAA receptors","volume":"148","author":"Chang","year":"2006","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/sj.bjp.0706251","article-title":"Benzodiazepine modulation of partial agonist efficacy and spontaneously active GABAA receptors supports an allosteric model of modulation","volume":"145","author":"Downing","year":"2005","journal-title":"Br. J. Pharmacol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S0304-3940(01)01646-9","article-title":"Allosteric modulation in spontaneously active mutant \u03b3-aminobutyric acidA receptors","volume":"305","author":"Findlay","year":"2001","journal-title":"Neurosci. Lett."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"64400","DOI":"10.7554\/eLife.64400","article-title":"A critical residue in the \u03b11M2\u2013M3 linker regulating mammalian GABAA receptor pore gating by diazepam","volume":"10","author":"Nors","year":"2021","journal-title":"eLife"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2542","DOI":"10.1016\/S0006-3495(99)77089-X","article-title":"Allosteric Activation Mechanism of the \u03b11\u03b22\u03b32 \u03b3-Aminobutyric Acid Type A Receptor Revealed by Mutation of the Conserved M2 Leucine","volume":"77","author":"Chang","year":"1999","journal-title":"Biophys. J."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"8411","DOI":"10.1523\/JNEUROSCI.22-19-08411.2002","article-title":"Coupled and uncoupled gating and desensitization effects by pore domain mutations in GABA(A) receptors","volume":"22","author":"Scheller","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1073\/pnas.0809272106","article-title":"Unliganded gating of acetylcholine receptor channels","volume":"106","author":"Purohit","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","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":"ref_93","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1085\/jgp.201210844","article-title":"Perspectives on: Conformational coupling in ion channels: Allosteric coupling in ligand-gated ion channels","volume":"140","author":"Colquhoun","year":"2012","journal-title":"J. Gen. Physiol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1085\/jgp.201210801","article-title":"An integrated catch-and-hold mechanism activates nicotinic acetylcholine receptors","volume":"140","author":"Jadey","year":"2012","journal-title":"J. Gen. Physiol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1085\/jgp.201611584","article-title":"Improved resolution of single channel dwell times reveals mechanisms of binding, priming, and gating in muscle AChR","volume":"148","author":"Mukhtasimova","year":"2016","journal-title":"J. Gen. Physiol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3193","DOI":"10.1523\/JNEUROSCI.2533-13.2014","article-title":"\u03b11F64 Residue at GABAA Receptor Binding Site Is Involved in Gating by Influencing the Receptor Flipping Transitions","volume":"34","author":"Szczot","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"5707","DOI":"10.1523\/JNEUROSCI.5663-11.2012","article-title":"Benzodiazepines Modulate GABAA Receptors by Regulating the Preactivation Step after GABA Binding","volume":"32","author":"Gielen","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1085\/jgp.201411183","article-title":"A nonequilibrium binary elements-based kinetic model for benzodiazepine regulation of GABAA receptors","volume":"144","author":"Haroldson","year":"2014","journal-title":"J. Gen. Physiol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"237","DOI":"10.3389\/fncel.2018.00237","article-title":"Distinct Modulation of Spontaneous and GABA-Evoked Gating by Flurazepam Shapes Cross-Talk Between Agonist-Free and Liganded GABAA Receptor Activity","volume":"12","author":"Terejko","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"ref_100","first-page":"3522","article-title":"Zolpidem and eszopiclone prime \u03b11\u03b22\u03b32 GABAA receptors for longer duration of activity","volume":"172","author":"Dixon","year":"2015","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1113\/jphysiol.2003.054734","article-title":"Activation of single heteromeric GABAA receptor ion channels by full and partial agonists","volume":"557","author":"Mortensen","year":"2004","journal-title":"J. Physiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.neuron.2016.03.032","article-title":"Emerging Molecular Mechanisms of Signal Transduction in Pentameric Ligand-Gated Ion Channels","volume":"90","author":"Nemecz","year":"2016","journal-title":"Neuron"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.tibs.2021.01.011","article-title":"Direct Structural Insights into GABAA Receptor Pharmacology","volume":"46","author":"Kim","year":"2021","journal-title":"Trends Biochem. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"8264","DOI":"10.1074\/jbc.RA118.002128","article-title":"An intersubunit electrostatic interaction in the GABAA receptor facilitates its responses to benzodiazepines","volume":"293","author":"Pflanz","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"6714","DOI":"10.1074\/jbc.M111.316836","article-title":"Structural Link between \u03b3-Aminobutyric Acid Type A (GABAA) Receptor Agonist Binding Site and Inner \u03b2-Sheet Governs Channel Activation and Allosteric Drug Modulation","volume":"287","author":"Venkatachalan","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"114338","DOI":"10.1016\/j.bcp.2020.114338","article-title":"Interaction between GABAA receptor \u03b11 and \u03b22 subunits at the N-terminal peripheral regions is crucial for receptor binding and gating","volume":"183","author":"Terejko","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1124\/mol.104.008151","article-title":"Benzodiazepines Affect Channel Opening of GABAA Receptors Induced by Either Agonist Binding Site","volume":"67","author":"Baur","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"ref_108","first-page":"35","article-title":"An Epilepsy-Related Region in the GABAA Receptor Mediates Long-Distance Effects on GABA and Benzodiazepine Binding Sites","volume":"77","author":"Wagner","year":"2009","journal-title":"Mol. Pharmacol."},{"key":"ref_109","doi-asserted-by":"crossref","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":"2021","journal-title":"Cell"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"3040","DOI":"10.1038\/emboj.2009.227","article-title":"Structural determinants for interaction of partial agonists with acetylcholine binding protein and neuronal \u03b17 nicotinic acetylcholine receptor","volume":"28","author":"Hibbs","year":"2009","journal-title":"EMBO J."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Stewart, D.S., Pierce, D.W., Hotta, M., Stern, A.T., and Forman, S.A. (2014). Mutations at Beta N265 in \u03b3-Aminobutyric Acid Type A Receptors Alter Both Binding Affinity and Efficacy of Potent Anesthetics. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0111470"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1124\/mol.58.5.1129","article-title":"Benzodiazepines Induce a Conformational Change in the Region of the \u03b3-Aminobutyric Acid Type A Receptor \u03b11-Subunit M3 Membrane-Spanning Segment","volume":"58","author":"Williams","year":"2000","journal-title":"Mol. Pharmacol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S0028-3908(01)00099-5","article-title":"Evidence for distinct conformations of the two \u03b11 subunits in diazepam-bound GABAA receptors","volume":"41","author":"Williams","year":"2001","journal-title":"Neuropharmacology"},{"key":"ref_114","first-page":"673","article-title":"Disulphide trapping of the GABAA receptor reveals the importance of the coupling interface in the action of benzodiazepines","volume":"162","author":"Hanson","year":"2011","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/nature01280","article-title":"Coupling of agonist binding to channel gating in the GABAA receptor","volume":"421","author":"Kash","year":"2003","journal-title":"Nature"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"4887","DOI":"10.1074\/jbc.M311441200","article-title":"Charged Residues in the \u03b22 Subunit Involved in GABAA Receptor Activation","volume":"279","author":"Kash","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"3490","DOI":"10.1523\/JNEUROSCI.5727-07.2008","article-title":"Structural Mechanisms Underlying Benzodiazepine Modulation of the GABAA Receptor","volume":"28","author":"Hanson","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2702","DOI":"10.1074\/jbc.M705699200","article-title":"The F-loop of the GABAA Receptor \u03b32 Subunit Contributes to Benzodiazepine Modulation","volume":"283","author":"Padgett","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1111\/j.1471-4159.2010.07052.x","article-title":"A residue close to \u03b11 loop F disrupts modulation of GABAA receptors by benzodiazepines while their binding is maintained","volume":"115","author":"Baur","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1113\/jphysiol.2009.179705","article-title":"The role of Loop F in the activation of the GABA receptor","volume":"588","author":"Khatri","year":"2010","journal-title":"J. Physiol."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Dellisanti, C.D., Ghosh, B., Hanson, S.M., Raspanti, J.M., Grant, V.A., Diarra, G.M., Schuh, A.M., Satyshur, K., Klug, C.S., and Czajkowski, C. (2013). Site-Directed Spin Labeling Reveals Pentameric Ligand-Gated Ion Channel Gating Motions. PLoS Biol., 11.","DOI":"10.1371\/journal.pbio.1001714"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1113\/JP275100","article-title":"The dual-gate model for pentameric ligand-gated ion channels activation and desensitization","volume":"596","author":"Gielen","year":"2018","journal-title":"J. Physiol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"6829","DOI":"10.1038\/ncomms7829","article-title":"The desensitization gate of inhibitory Cys-loop receptors","volume":"6","author":"Gielen","year":"2015","journal-title":"Nat. Commun."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/12\/1784\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:29:54Z","timestamp":1760146194000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/12\/1784"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,30]]},"references-count":123,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["biom12121784"],"URL":"https:\/\/doi.org\/10.3390\/biom12121784","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,30]]}}}