{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T23:30:27Z","timestamp":1780615827836,"version":"3.54.1"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T00:00:00Z","timestamp":1631664000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T00:00:00Z","timestamp":1631664000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000265","name":"RCUK | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/T002581\/1"],"award-info":[{"award-number":["MR\/T002581\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT 217199\/Z\/19\/Z"],"award-info":[{"award-number":["WT 217199\/Z\/19\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>GABA<jats:sub>A<\/jats:sub> receptors are vital for controlling neuronal excitability and can display significant levels of constitutive activity that contributes to tonic inhibition. However, the mechanisms underlying spontaneity are poorly understood. Here we demonstrate a strict requirement for \u03b23 subunit incorporation into receptors for spontaneous gating, facilitated by \u03b14, \u03b16 and \u03b4 subunits. The crucial molecular determinant involves four amino acids (GKER) in the \u03b23 subunit\u2019s extracellular domain, which interacts with adjacent receptor subunits to promote transition to activated, open channel conformations. Spontaneous activity is further regulated by \u03b23 subunit phosphorylation and by allosteric modulators including neurosteroids and benzodiazepines. Promoting spontaneous activity reduced neuronal excitability, indicating that spontaneous currents will alter neural network activity. This study demonstrates how regional diversity in GABA<jats:sub>A<\/jats:sub> receptor isoform, protein kinase activity, and neurosteroid levels, can impact on tonic inhibition through the modulation of spontaneous GABA<jats:sub>A<\/jats:sub> receptor gating.<\/jats:p>","DOI":"10.1038\/s41467-021-25633-0","type":"journal-article","created":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T10:03:59Z","timestamp":1631700239000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Structural determinants and regulation of spontaneous activity in GABAA receptors"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7617-8361","authenticated-orcid":false,"given":"Craig A.","family":"Sexton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2171-0872","authenticated-orcid":false,"given":"Reka","family":"Penzinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Mortensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian P.","family":"Bright","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9089-5375","authenticated-orcid":false,"given":"Trevor G.","family":"Smart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,15]]},"reference":[{"key":"25633_CR1","doi-asserted-by":"publisher","first-page":"40224","DOI":"10.1074\/jbc.R112.386664","volume":"287","author":"E Sigel","year":"2012","unstructured":"Sigel, E. & Steinmann, M. E. Structure, function, and modulation of GABAA receptors. J. Biol. Chem. 287, 40224\u201340231 (2012).","journal-title":"J. Biol. Chem."},{"key":"25633_CR2","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/nrn1625","volume":"6","author":"M Farrant","year":"2005","unstructured":"Farrant, M. & Nusser, Z. Variations on an inhibitory theme: phasic and tonic activation of GABAA receptors. Nat. Rev. Neurosci. 6, 215\u2013229 (2005).","journal-title":"Nat. Rev. Neurosci."},{"key":"25633_CR3","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.neuropharm.2008.07.045","volume":"56","author":"RW Olsen","year":"2009","unstructured":"Olsen, R. W. & Sieghart, W. GABAA receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology 56, 141\u2013148 (2009).","journal-title":"Neuropharmacology"},{"key":"25633_CR4","doi-asserted-by":"publisher","first-page":"46020","DOI":"10.1074\/jbc.M207663200","volume":"277","author":"SW Baumann","year":"2002","unstructured":"Baumann, S. W., Baur, R. & Sigel, E. Forced subunit assembly in \u03b11\u03b22\u03b32 GABAA receptors. Insight into the absolute arrangement. J. Biol. Chem. 277, 46020\u201346025 (2002).","journal-title":"J. Biol. Chem."},{"key":"25633_CR5","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1038\/s41586-018-0833-4","volume":"565","author":"D Laverty","year":"2019","unstructured":"Laverty, D. et al. Cryo-EM structure of the human \u03b11\u03b23\u03b32 GABAA receptor in a lipid bilayer. Nature 565, 516\u2013520 (2019).","journal-title":"Nature"},{"key":"25633_CR6","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1023\/A:1012376215967","volume":"26","author":"I Mody","year":"2001","unstructured":"Mody, I. Distinguishing between GABAA receptors responsible for tonic and phasic conductances. Neurochem. Res. 26, 907\u2013913 (2001).","journal-title":"Neurochem. Res."},{"key":"25633_CR7","doi-asserted-by":"publisher","first-page":"3662","DOI":"10.1073\/pnas.0307231101","volume":"101","author":"VB Caraiscos","year":"2004","unstructured":"Caraiscos, V. B. et al. Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by \u03b15 subunit-containing \u03b3-aminobutyric acid type A receptors. Proc. Natl Acad. Sci. USA 101, 3662\u20133667 (2004).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"25633_CR8","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1093\/cercor\/bhm160","volume":"18","author":"AB Ali","year":"2008","unstructured":"Ali, A. B. & Thomson, A. M. Synaptic \u03b15 subunit-containing GABAA receptors mediate IPSPs elicited by dendrite-preferring cells in rat neocortex. Cereb. Cortex 18, 1260\u20131271 (2008).","journal-title":"Cereb. Cortex"},{"key":"25633_CR9","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1113\/jphysiol.1996.sp021806","volume":"497","author":"SG Brickley","year":"1996","unstructured":"Brickley, S. G., Cull-Candy, S. G. & Farrant, M. Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors. J. Physiol. 497, 753\u2013759 (1996).","journal-title":"J. Physiol."},{"key":"25633_CR10","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/j.1469-7793.1999.027af.x","volume":"514","author":"KF Haas","year":"1999","unstructured":"Haas, K. F. & Macdonald, R. L. GABAA receptor subunit \u03b32 and \u03b4 subtypes confer unique kinetic properties on recombinant GABAA receptor currents in mouse fibroblasts. J. Physiol. 514, 27\u201345 (1999).","journal-title":"J. Physiol."},{"key":"25633_CR11","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/s002320001028","volume":"174","author":"B Birnir","year":"2000","unstructured":"Birnir, B., Everitt, A. B., Lim, M. S. & Gage, P. W. Spontaneously opening GABAA channels in CA1 pyramidal neurones of rat hippocampus. J. Membr. Biol. 174, 21\u201329 (2000).","journal-title":"J. Membr. Biol."},{"key":"25633_CR12","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1124\/mol.106.028597","volume":"71","author":"MR McCartney","year":"2007","unstructured":"McCartney, M. R., Deeb, T. Z., Henderson, T. N. & Hales, T. G. Tonically active GABAA receptors in hippocampal pyramidal neurons exhibit constitutive GABA-independent gating. Mol. Pharmacol. 71, 539\u2013548 (2007).","journal-title":"Mol. Pharmacol."},{"key":"25633_CR13","doi-asserted-by":"publisher","first-page":"3905","DOI":"10.1523\/JNEUROSCI.4193-12.2013","volume":"33","author":"AI Wlodarczyk","year":"2013","unstructured":"Wlodarczyk, A. I. et al. GABA-independent GABAA receptor openings maintain tonic currents. J. Neurosci. 33, 3905\u20133914 (2013).","journal-title":"J. Neurosci."},{"key":"25633_CR14","doi-asserted-by":"publisher","first-page":"2225","DOI":"10.1111\/j.1460-9568.1997.tb01641.x","volume":"9","author":"JR Wooltorton","year":"1997","unstructured":"Wooltorton, J. R., Moss, S. J. & Smart, T. G. Pharmacological and physiological characterization of murine homomeric \u03b23 GABAA receptors. Eur. J. Neurosci. 9, 2225\u20132235 (1997).","journal-title":"Eur. J. Neurosci."},{"key":"25633_CR15","first-page":"494","volume":"49","author":"BJ Krishek","year":"1996","unstructured":"Krishek, B. J., Moss, S. J. & Smart, T. G. Homomeric \u03b21 \u03b3-aminobutyric acid A receptor-ion channels: evaluation of pharmacological and physiological properties. Mol. Pharmacol. 49, 494\u2013504 (1996).","journal-title":"Mol. Pharmacol."},{"key":"25633_CR16","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.ejphar.2004.06.004","volume":"496","author":"CE Lindquist","year":"2004","unstructured":"Lindquist, C. E., Dalziel, J. E., Cromer, B. A. & Birnir, B. Penicillin blocks human \u03b11\u03b21 and \u03b11\u03b21\u03b32S GABAA channels that open spontaneously. Eur. J. Pharmacol. 496, 23\u201332 (2004).","journal-title":"Eur. J. Pharmacol."},{"key":"25633_CR17","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1124\/mol.55.1.168","volume":"55","author":"TR Neelands","year":"1999","unstructured":"Neelands, T. R., Fisher, J. L., Bianchi, M. & Macdonald, R. L. Spontaneous and \u03b3-aminobutyric acid (GABA)-activated GABAA receptor channels formed by \u03b5 subunit-containing isoforms. Mol. Pharmacol. 55, 168\u2013178 (1999).","journal-title":"Mol. Pharmacol."},{"key":"25633_CR18","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1152\/jn.00801.2009","volume":"103","author":"X Tang","year":"2010","unstructured":"Tang, X., Hernandez, C. C. & Macdonald, R. L. Modulation of spontaneous and GABA-evoked tonic \u03b14\u03b23\u03b4 and \u03b14\u03b23\u03b32L GABAA receptor currents by protein kinase A. J. Neurophysiol. 103, 1007\u20131019 (2010).","journal-title":"J. Neurophysiol."},{"key":"25633_CR19","doi-asserted-by":"publisher","first-page":"237","DOI":"10.3389\/fncel.2018.00237","volume":"12","author":"M Jatczak-Sliwa","year":"2018","unstructured":"Jatczak-Sliwa, M. et al. Distinct modulation of spontaneous and GABA-evoked gating by flurazepam shapes cross-talk between agonist-free and liganded GABAA receptor activity. Front. Cell. Neurosci. 12, 237 (2018).","journal-title":"Front. Cell. Neurosci."},{"key":"25633_CR20","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0856-7","volume":"9","author":"N O\u2019Neill","year":"2018","unstructured":"O\u2019Neill, N. & Sylantyev, S. Spontaneously opening GABAA receptors play a significant role in neuronal signal filtering and integration. Cell Death Dis. 9, 813 (2018).","journal-title":"Cell Death Dis."},{"key":"25633_CR21","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/S0896-6273(03)00200-9","volume":"38","author":"SJ Mitchell","year":"2003","unstructured":"Mitchell, S. J. & Silver, R. A. Shunting inhibition modulates neuronal gain during synaptic excitation. Neuron 38, 433\u2013445 (2003).","journal-title":"Neuron"},{"key":"25633_CR22","doi-asserted-by":"publisher","first-page":"3","DOI":"10.3389\/fncir.2014.00003","volume":"8","author":"V Lee","year":"2014","unstructured":"Lee, V. & Maguire, J. The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type. Front. Neural Circuits 8, https:\/\/doi.org\/10.3389\/fncir.2014.00003 (2014).","journal-title":"Front. Neural Circuits"},{"key":"25633_CR23","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1038\/nrn2864","volume":"11","author":"RA Silver","year":"2010","unstructured":"Silver, R. A. Neuronal arithmetic. Nat. Rev. Neurosci. 11, 474\u2013489 (2010).","journal-title":"Nat. Rev. Neurosci."},{"key":"25633_CR24","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1113\/jphysiol.2009.182444","volume":"588","author":"M Mortensen","year":"2010","unstructured":"Mortensen, M., Ebert, B., Wafford, K. & Smart, T. G. Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors. J. Physiol. 588, 1251\u20131268 (2010).","journal-title":"J. Physiol."},{"key":"25633_CR25","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1124\/jpet.105.092403","volume":"316","author":"SI Storustovu","year":"2006","unstructured":"Storustovu, S. I. & Ebert, B. Pharmacological characterization of agonists at \u03b4-containing GABAA receptors: Functional selectivity for extrasynaptic receptors is dependent on the absence of \u03b32. J. Pharmacol. Exp. Ther. 316, 1351\u20131359 (2006).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"25633_CR26","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1111\/bph.12001","volume":"168","author":"ML Jensen","year":"2013","unstructured":"Jensen, M. L. et al. A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABAA receptors. Br. J. Pharmacol. 168, 1118\u20131132 (2013).","journal-title":"Br. J. Pharmacol."},{"key":"25633_CR27","doi-asserted-by":"publisher","first-page":"6360","DOI":"10.1523\/JNEUROSCI.19-15-06360.1999","volume":"19","author":"PM Taylor","year":"1999","unstructured":"Taylor, P. M. et al. Identification of amino acid residues within GABAA receptor \u03b2 subunits that mediate both homomeric and heteromeric receptor expression. J. Neurosci. 19, 6360\u20136371 (1999).","journal-title":"J. Neurosci."},{"key":"25633_CR28","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1124\/mol.114.094813","volume":"86","author":"MM Eaton","year":"2014","unstructured":"Eaton, M. M. et al. \u03b3-aminobutyric acid type A \u03b14, \u03b22, and \u03b4 subunits assemble to produce more than one functionally distinct receptor type. Mol. Pharmacol. 86, 647\u2013656 (2014).","journal-title":"Mol. Pharmacol."},{"key":"25633_CR29","doi-asserted-by":"publisher","first-page":"18474","DOI":"10.1074\/jbc.M116.738906","volume":"291","author":"N Wongsamitkul","year":"2016","unstructured":"Wongsamitkul, N., Baur, R. & Sigel, E. Toward understanding functional properties and subunit arrangement of \u03b14\u03b22\u03b4 \u03b3-aminobutyric acid, type A (GABAA) receptors. J. Biol. Chem. 291, 18474\u201318483 (2016).","journal-title":"J. Biol. Chem."},{"key":"25633_CR30","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1124\/mol.107.042481","volume":"73","author":"NP Barrera","year":"2008","unstructured":"Barrera, N. P. et al. Atomic force microscopy reveals the stoichiometry and subunit arrangement of the \u03b14\u03b23\u03b4 GABAA receptor. Mol. Pharmacol. 73, 960\u2013967 (2008).","journal-title":"Mol. Pharmacol."},{"key":"25633_CR31","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1111\/bph.12514","volume":"171","author":"B Patel","year":"2014","unstructured":"Patel, B., Mortensen, M. & Smart, T. G. Stoichiometry of \u03b4 subunit containing GABAA receptors. Br. J. Pharmacol. 171, 985\u2013994 (2014).","journal-title":"Br. J. Pharmacol."},{"key":"25633_CR32","doi-asserted-by":"publisher","first-page":"1426","DOI":"10.1016\/S0021-9258(18)45961-3","volume":"267","author":"HA Wieland","year":"1992","unstructured":"Wieland, H. A., Luddens, H. & Seeburg, P. H. A single histidine in GABAA receptors is essential for benzodiazepine agonist binding. J. Biol. Chem. 267, 1426\u20131429 (1992).","journal-title":"J. Biol. Chem."},{"key":"25633_CR33","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1124\/mol.117.110569","volume":"93","author":"G Akk","year":"2018","unstructured":"Akk, G., Shin, D. J., Germann, A. L. & Steinbach, J. H. GABA type A receptor activation in the allosteric coagonist model framework: relationship between EC50 and basal activity. Mol. Pharmacol. 93, 90\u2013100 (2018).","journal-title":"Mol. Pharmacol."},{"key":"25633_CR34","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1006\/mcne.2002.1143","volume":"20","author":"JL Fisher","year":"2002","unstructured":"Fisher, J. L. A lysine residue in the \u03b23 subunit contributes to the regulation of GABAA receptor activity by voltage. Mol. Cell. Neurosci. 20, 683\u2013694 (2002).","journal-title":"Mol. Cell. Neurosci."},{"key":"25633_CR35","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/j.neuron.2011.03.024","volume":"70","author":"B Luscher","year":"2011","unstructured":"Luscher, B., Fuchs, T. & Kilpatrick, C. L. GABAA receptor trafficking-mediated plasticity of inhibitory synapses. Neuron 70, 385\u2013409 (2011).","journal-title":"Neuron"},{"key":"25633_CR36","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/223","volume":"1","author":"BJ McDonald","year":"1998","unstructured":"McDonald, B. J. et al. Adjacent phosphorylation sites on GABAA receptor \u03b2 subunits determine regulation by cAMP-dependent protein kinase. Nat. Neurosci. 1, 23\u201328 (1998).","journal-title":"Nat. Neurosci."},{"key":"25633_CR37","doi-asserted-by":"publisher","first-page":"38856","DOI":"10.1074\/jbc.M004910200","volume":"275","author":"NJ Brandon","year":"2000","unstructured":"Brandon, N. J. et al. GABAA receptor phosphorylation and functional modulation in cortical neurons by a protein kinase C-dependent pathway. J. Biol. Chem. 275, 38856\u201338862 (2000).","journal-title":"J. Biol. Chem."},{"key":"25633_CR38","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/bs.apha.2014.11.008","volume":"72","author":"Y Nakamura","year":"2015","unstructured":"Nakamura, Y., Darnieder, L. M., Deeb, T. Z. & Moss, S. J. Regulation of GABAARs by phosphorylation. Adv. Pharmacol. 72, 97\u2013146 (2015).","journal-title":"Adv. Pharmacol."},{"key":"25633_CR39","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1016\/S0028-3908(97)00111-1","volume":"36","author":"BJ McDonald","year":"1997","unstructured":"McDonald, B. J. & Moss, S. J. Conserved phosphorylation of the intracellular domains of GABAA receptor \u03b22 and \u03b23 subunits by cAMP-dependent protein kinase, cGMP-dependent protein kinase, protein kinase C and Ca2+\/calmodulin type II-dependent protein kinase. Neuropharmacology 36, 1377\u20131385 (1997).","journal-title":"Neuropharmacology"},{"key":"25633_CR40","doi-asserted-by":"publisher","first-page":"17855","DOI":"10.1074\/jbc.M611533200","volume":"282","author":"CM Houston","year":"2007","unstructured":"Houston, C. M., Lee, H. H., Hosie, A. M., Moss, S. J. & Smart, T. G. Identification of the sites for CaMK-II-dependent phosphorylation of GABAA receptors. J. Biol. Chem. 282, 17855\u201317865 (2007).","journal-title":"J. Biol. Chem."},{"key":"25633_CR41","doi-asserted-by":"publisher","first-page":"2504","DOI":"10.1111\/j.1460-9568.2006.05145.x","volume":"24","author":"CM Houston","year":"2006","unstructured":"Houston, C. M. & Smart, T. G. CaMK-II modulation of GABAA receptors expressed in HEK293, NG108-15 and rat cerebellar granule neurons. Eur. J. Neurosci. 24, 2504\u20132514 (2006).","journal-title":"Eur. J. Neurosci."},{"key":"25633_CR42","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/s00213-013-3276-5","volume":"230","author":"CM Carver","year":"2013","unstructured":"Carver, C. M. & Reddy, D. S. Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability. Psychopharmacology 230, 151\u2013188 (2013).","journal-title":"Psychopharmacology"},{"key":"25633_CR43","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/nature05324","volume":"444","author":"AM Hosie","year":"2006","unstructured":"Hosie, A. M., Wilkins, M. E., da Silva, H. M. & Smart, T. G. Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature 444, 486\u2013489 (2006).","journal-title":"Nature"},{"key":"25633_CR44","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1038\/nsmb.3477","volume":"24","author":"D Laverty","year":"2017","unstructured":"Laverty, D. et al. Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites. Nat. Struct. Mol. Biol. 24, 977\u2013985 (2017).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"25633_CR45","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.neuropharm.2018.02.008","volume":"136","author":"S Seljeset","year":"2018","unstructured":"Seljeset, S., Bright, D. P., Thomas, P. & Smart, T. G. Probing GABAA receptors with inhibitory neurosteroids. Neuropharmacology 136, 23\u201336 (2018).","journal-title":"Neuropharmacology"},{"key":"25633_CR46","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.neuropharm.2018.01.036","volume":"136","author":"RW Olsen","year":"2018","unstructured":"Olsen, R. W. GABAA receptor: positive and negative allosteric modulators. Neuropharmacology 136, 10\u201322 (2018).","journal-title":"Neuropharmacology"},{"key":"25633_CR47","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1016\/j.tips.2018.03.006","volume":"39","author":"E Sigel","year":"2018","unstructured":"Sigel, E. & Ernst, M. The benzodiazepine binding sites of GABAA receptors. Trends Pharmacol. Sci. 39, 659\u2013671 (2018).","journal-title":"Trends Pharmacol. Sci."},{"key":"25633_CR48","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1038\/s41586-018-0832-5","volume":"565","author":"S Masiulis","year":"2019","unstructured":"Masiulis, S. et al. GABAA receptor signalling mechanisms revealed by structural pharmacology. Nature 565, 454\u2013459 (2019).","journal-title":"Nature"},{"key":"25633_CR49","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1016\/S0306-4522(00)00442-5","volume":"101","author":"S Pirker","year":"2000","unstructured":"Pirker, S., Schwarzer, C., Wieselthaler, A., Sieghart, W. & Sperk, G. GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience 101, 815\u2013850 (2000).","journal-title":"Neuroscience"},{"key":"25633_CR50","doi-asserted-by":"publisher","first-page":"11553","DOI":"10.1523\/JNEUROSCI.3362-05.2005","volume":"25","author":"DW Cope","year":"2005","unstructured":"Cope, D. W., Hughes, S. W. & Crunelli, V. GABAA receptor-mediated tonic inhibition in thalamic neurons. J. Neurosci. 25, 11553\u201311563 (2005).","journal-title":"J. Neurosci."},{"key":"25633_CR51","doi-asserted-by":"publisher","first-page":"14439","DOI":"10.1073\/pnas.2435457100","volume":"100","author":"BM Stell","year":"2003","unstructured":"Stell, B. M., Brickley, S. G., Tang, C. Y., Farrant, M. & Mody, I. Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by \u03b4 subunit-containing GABAA receptors. Proc. Natl Acad. Sci. USA 100, 14439\u201314444 (2003).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"25633_CR52","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1113\/jphysiol.2007.132886","volume":"581","author":"SH Hadley","year":"2007","unstructured":"Hadley, S. H. & Amin, J. Rat \u03b16\u03b22\u03b4 GABAA receptors exhibit two distinct and separable agonist affinities. J. Physiol. 581, 1001\u20131018 (2007).","journal-title":"J. Physiol."},{"key":"25633_CR53","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-52573-z","volume":"9","author":"SR Pierce","year":"2019","unstructured":"Pierce, S. R., Senneff, T. C., Germann, A. L. & Akk, G. Steady-state activation of the high-affinity isoform of the \u03b14\u03b22\u03b4 GABAA receptor. Sci. Rep. 9, 15997 (2019).","journal-title":"Sci. Rep."},{"key":"25633_CR54","doi-asserted-by":"publisher","first-page":"9899","DOI":"10.1073\/pnas.93.18.9899","volume":"93","author":"CN Connolly","year":"1996","unstructured":"Connolly, C. N., Wooltorton, J. R., Smart, T. G. & Moss, S. J. Subcellular localization of \u03b3-aminobutyric acid type A receptors is determined by receptor \u03b2 subunits. Proc. Natl Acad. Sci. USA 93, 9899\u20139904 (1996).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"25633_CR55","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1111\/j.1476-5381.2011.01779.x","volume":"166","author":"W Sieghart","year":"2012","unstructured":"Sieghart, W., Ramerstorfer, J., Sarto-Jackson, I., Varagic, Z. & Ernst, M. A novel GABAA receptor pharmacology: drugs interacting with the \u03b1+\u03b2\u2212 interface. Br. J. Pharmacol. 166, 476\u2013485 (2012).","journal-title":"Br. J. Pharmacol."},{"key":"25633_CR56","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1111\/bph.12151","volume":"169","author":"Z Varagic","year":"2013","unstructured":"Varagic, Z. et al. Identification of novel positive allosteric modulators and null modulators at the GABAA receptor \u03b1+\u03b2\u2212 interface. Br. J. Pharmacol. 169, 371\u2013383 (2013).","journal-title":"Br. J. Pharmacol."},{"key":"25633_CR57","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1113\/jphysiol.2009.179705","volume":"588","author":"A Khatri","year":"2010","unstructured":"Khatri, A. & Weiss, D. S. The role of Loop F in the activation of the GABA receptor. J. Physiol. 588, 59\u201366 (2010).","journal-title":"J. Physiol."},{"key":"25633_CR58","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1016\/j.neuropharm.2017.10.042","volume":"128","author":"A Palvolgyi","year":"2018","unstructured":"Palvolgyi, A. et al. Loop F of the GABAA receptor alpha subunit governs GABA potency. Neuropharmacology 128, 408\u2013415 (2018).","journal-title":"Neuropharmacology"},{"key":"25633_CR59","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1113\/jphysiol.2008.160093","volume":"587","author":"J Zhang","year":"2009","unstructured":"Zhang, J., Xue, F. & Chang, Y. Agonist- and antagonist-induced conformational changes of loop F and their contributions to the \u03c11 GABA receptor function. J. Physiol. 587, 139\u2013153 (2009).","journal-title":"J. Physiol."},{"key":"25633_CR60","doi-asserted-by":"publisher","first-page":"7281","DOI":"10.1074\/jbc.M109.050294","volume":"285","author":"CA Williams","year":"2010","unstructured":"Williams, C. A., Bell, S. V. & Jenkins, A. A residue in loop 9 of the \u03b22-subunit stabilizes the closed state of the GABAA receptor. J. Biol. Chem. 285, 7281\u20137287 (2010).","journal-title":"J. Biol. Chem."},{"key":"25633_CR61","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3816","volume":"4","author":"QM Anstee","year":"2013","unstructured":"Anstee, Q. M. et al. Mutations in the GABRB1 gene promote alcohol consumption through increased tonic inhibition. Nat. Commun. 4, 2816 (2013).","journal-title":"Nat. Commun."},{"key":"25633_CR62","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1152\/jn.00951.2002","volume":"89","author":"JW Mozrzymas","year":"2003","unstructured":"Mozrzymas, J. W., Barberis, A., Mercik, K. & Zarnowska, E. D. Binding sites, singly bound states, and conformation coupling shape GABA-evoked currents. J. Neurophysiol. 89, 871\u2013883 (2003).","journal-title":"J. Neurophysiol."},{"key":"25633_CR63","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1085\/jgp.201812215","volume":"151","author":"TK Nayak","year":"2019","unstructured":"Nayak, T. K., Vij, R., Bruhova, I., Shandilya, J. & Auerbach, A. Efficiency measures the conversion of agonist binding energy into receptor conformational change. J. Gen. Physiol. 151, 465\u2013477 (2019).","journal-title":"J. Gen. Physiol."},{"key":"25633_CR64","doi-asserted-by":"publisher","first-page":"2560","DOI":"10.1523\/JNEUROSCI.5100-06.2007","volume":"27","author":"DP Bright","year":"2007","unstructured":"Bright, D. P., Aller, M. I. & Brickley, S. G. Synaptic release generates a tonic GABAA receptor-mediated conductance that modulates burst precision in thalamic relay neurons. J. Neurosci. 27, 2560\u20132569 (2007).","journal-title":"J. Neurosci."},{"key":"25633_CR65","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1016\/j.neuroscience.2010.02.048","volume":"167","author":"V Santhakumar","year":"2010","unstructured":"Santhakumar, V., Jones, R. T. & Mody, I. Developmental regulation and neuroprotective effects of striatal tonic GABAA currents. Neuroscience 167, 644\u2013655 (2010).","journal-title":"Neuroscience"},{"key":"25633_CR66","doi-asserted-by":"publisher","unstructured":"Janssen, M., Yasuda, R. & Vicini, S. GABAA receptor \u03b23 subunit expression regulates tonic current in developing striatopallidal medium spiny neurons. Front. Cell. Neurosci. 5, https:\/\/doi.org\/10.3389\/fncel.2011.00015 (2011).","DOI":"10.3389\/fncel.2011.00015"},{"key":"25633_CR67","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.neuropharm.2014.09.021","volume":"88","author":"JM Adams","year":"2015","unstructured":"Adams, J. M., Thomas, P. & Smart, T. G. Modulation of neurosteroid potentiation by protein kinases at synaptic- and extrasynaptic-type GABAA receptors. Neuropharmacology 88, 63\u201373 (2015).","journal-title":"Neuropharmacology"},{"key":"25633_CR68","doi-asserted-by":"publisher","first-page":"3780","DOI":"10.1523\/JNEUROSCI.4989-12.2013","volume":"33","author":"WM Connelly","year":"2013","unstructured":"Connelly, W. M. et al. GABAB receptors regulate extrasynaptic GABAA receptors. J. Neurosci. 33, 3780\u20133785 (2013).","journal-title":"J. Neurosci."},{"key":"25633_CR69","doi-asserted-by":"publisher","first-page":"4143","DOI":"10.1073\/pnas.94.8.4143","volume":"94","author":"GE Homanics","year":"1997","unstructured":"Homanics, G. E. et al. Mice devoid of \u03b3-aminobutyrate type A receptor \u03b23 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc. Natl Acad. Sci. USA 94, 4143\u20134148 (1997).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"25633_CR70","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1212\/WNL.0000000000003565","volume":"88","author":"RS M\u00f8ller","year":"2017","unstructured":"M\u00f8ller, R. S. et al. Mutations in GABRB3: from febrile seizures to epileptic encephalopathies. Neurology 88, 483\u2013492 (2017).","journal-title":"Neurology"},{"key":"25633_CR71","doi-asserted-by":"publisher","first-page":"2826","DOI":"10.1038\/nprot.2007.403","volume":"2","author":"M Mortensen","year":"2007","unstructured":"Mortensen, M. & Smart, T. G. Single-channel recording of ligand-gated ion channels. Nat. Protoc. 2, 2826\u20132841 (2007).","journal-title":"Nat. Protoc."},{"key":"25633_CR72","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1002\/prot.22488","volume":"77","author":"GG Krivov","year":"2009","unstructured":"Krivov, G. G., Shapovalov, M. V. & Dunbrack, R. L. Jr. Improved prediction of protein side-chain conformations with SCWRL4. Proteins 77, 778\u2013795 (2009).","journal-title":"Proteins"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-25633-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-25633-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-25633-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T14:42:15Z","timestamp":1669992135000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-25633-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,15]]},"references-count":72,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["25633"],"URL":"https:\/\/doi.org\/10.1038\/s41467-021-25633-0","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,15]]},"assertion":[{"value":"19 May 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5457"}}