{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T11:34:48Z","timestamp":1770464088255,"version":"3.49.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T00:00:00Z","timestamp":1673913600000},"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. Mol. Neurosci."],"abstract":"<jats:p>The <jats:italic>Gelsemium elegans<\/jats:italic> plant preparations have shown beneficial activity against common diseases, including chronic pain and anxiety. Nevertheless, their clinical uses are limited by their toxicity. Gelsemine, one of the most abundant alkaloids in the <jats:italic>Gelsemium<\/jats:italic> plants, have replicated these therapeutic and toxic actions in experimental behavioral models. However, the molecular targets underlying these biological effects remain unclear. The behavioral activity profile of gelsemine suggests the involvement of GABA<jats:sub>A<\/jats:sub> receptors (GABA<jats:sub>A<\/jats:sub>Rs), which are the main biological targets of benzodiazepines (BDZs), a group of drugs with anxiolytic, hypnotic, and analgesic properties. Here, we aim to define the modulation of GABA<jats:sub>A<\/jats:sub>Rs by gelsemine, with a special focus on the subtypes involved in the BDZ actions. The gelsemine actions were determined by electrophysiological recordings of recombinant GABA<jats:sub>A<\/jats:sub>Rs expressed in HEK293 cells, and of native receptors in cortical neurons. Gelsemine inhibited the agonist-evoked currents of recombinant and native receptors. The functional inhibition was not associated with the BDZ binding site. We determined in addition that gelsemine diminished the frequency of GABAergic synaptic events, likely through a presynaptic modulation. Our findings establish gelsemine as a negative modulator of GABA<jats:sub>A<\/jats:sub>Rs and of GABAergic synaptic function. These pharmacological features discard direct anxiolytic or analgesic actions of gelsemine through GABA<jats:sub>A<\/jats:sub>Rs but support a role of GABA<jats:sub>A<\/jats:sub>Rs on the alkaloid induced toxicity. On the other hand, the presynaptic effects of the alkaloid provide an additional mechanism to explain their beneficial effects. Collectively, our results contribute novel information to improve understanding of gelsemine actions in the mammalian nervous system.<\/jats:p>","DOI":"10.3389\/fnmol.2022.1083189","type":"journal-article","created":{"date-parts":[[2023,1,17]],"date-time":"2023-01-17T05:19:39Z","timestamp":1673932779000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Modulation of GABAA receptors and of GABAergic synapses by the natural alkaloid gelsemine"],"prefix":"10.3389","volume":"15","author":[{"given":"Ana M.","family":"Marileo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javiera","family":"Gavil\u00e1n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria P.","family":"San Mart\u00edn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cesar O.","family":"Lara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anggelo","family":"Sazo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carola","family":"Mu\u00f1oz-Montesino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricio A.","family":"Castro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos F.","family":"Burgos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"El\u00edas","family":"Leiva-Salcedo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis G.","family":"Aguayo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gustavo","family":"Moraga-Cid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Fuentealba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gonzalo E.","family":"Y\u00e9venes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,17]]},"reference":[{"key":"ref1","first-page":"61","article-title":"Ethanol modulation of the gamma-aminobutyric acidA- and glycine-activated Cl- current in cultured mouse neurons","volume":"270","author":"Aguayo","year":"1994","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"83","DOI":"10.3389\/fncel.2020.00083","article-title":"Pregabalin as a pain therapeutic: beyond calcium channels","volume":"14","author":"Alles","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1016\/j.celrep.2013.07.016","article-title":"Glycine receptor \u03b12 subunit activation promotes cortical interneuron migration","volume":"4","author":"Avila","year":"2013","journal-title":"Cell Rep."},{"key":"ref4","doi-asserted-by":"publisher","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":"ref5","doi-asserted-by":"publisher","first-page":"e51156","DOI":"10.7554\/eLife.51156","article-title":"Presynaptic GABA(B) receptors functionally uncouple somatostatin interneurons from the active hippocampal network","volume":"9","author":"Booker","year":"2020","journal-title":"eLife"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"108035","DOI":"10.1016\/j.pharmthera.2021.108035","article-title":"GABAkines \u2013 Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors","volume":"234","author":"Cerne","year":"2022","journal-title":"Pharmacol. Ther."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"954302","DOI":"10.1155\/2013\/954302","article-title":"Presynaptic glycine receptors increase GABAergic neurotransmission in rat periaqueductal gray neurons","volume":"2013","author":"Choi","year":"2013","journal-title":"Neural Plast."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"185","DOI":"10.4103\/0973-7847.70916","article-title":"The genus Gelsemium: an update","volume":"4","author":"Dutt","year":"2010","journal-title":"Pharmacogn. Rev."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/bs.apha.2014.11.006","article-title":"Significance of GABA(a) receptor heterogeneity: clues from developing neurons","volume":"73","author":"Fritschy","year":"2015","journal-title":"Adv. Pharmacol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1186\/s43141-021-00224-0","article-title":"GABA(A) receptors: structure, function, pharmacology, and related disorders","volume":"19","author":"Ghit","year":"2021","journal-title":"J. Genet. Eng. Biotechnol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.neuroscience.2005.11.001","article-title":"Presynaptic GABAA receptors facilitate spontaneous glutamate release from presynaptic terminals on mechanically dissociated rat CA3 pyramidal neurons","volume":"138","author":"Jang","year":"2006","journal-title":"Neuroscience"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.jep.2014.01.003","article-title":"Medicinal plants of the genus Gelsemium (Gelsemiaceae, Gentianales) a review of their phytochemistry, pharmacology, toxicology and traditional use","volume":"152","author":"Jin","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref13","doi-asserted-by":"publisher","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":"ref14","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.coph.2021.04.003","article-title":"Pharmacological modulation of GABA(a) receptors","volume":"59","author":"Knoflach","year":"2021","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"167","DOI":"10.3389\/fphar.2020.00167","article-title":"Pentameric ligand-gated ion channels as pharmacological targets against chronic pain","volume":"11","author":"Lara","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"2263","DOI":"10.1111\/bph.13507","article-title":"Functional modulation of glycine receptors by the alkaloid gelsemine","volume":"173","author":"Lara","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"9603271211062857","DOI":"10.1177\/09603271211062857","article-title":"Toxicity assessment of gelsenicine and the search for effective antidotes","volume":"41","author":"Li","year":"2022","journal-title":"Hum. Exp. Toxicol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"7145","DOI":"10.3390\/molecules26237145","article-title":"Gelsemium elegans Benth: chemical components, pharmacological effects, and toxicity mechanisms","volume":"26","author":"Lin","year":"2021","journal-title":"Molecules"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1007\/s00213-012-2867-x","article-title":"The active alkaloids of Gelsemium elegans Benth. Are potent anxiolytics","volume":"225","author":"Liu","year":"2013","journal-title":"Psychopharmacology"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"E7179","DOI":"10.1073\/pnas.1703839114","article-title":"Glycine receptor \u03b13 and \u03b12 subunits mediate tonic and exogenous agonist-induced currents in forebrain","volume":"114","author":"McCracken","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"3189","DOI":"10.1111\/bph.12955","article-title":"Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP","volume":"172","author":"McGrath","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.bbr.2013.07.010","article-title":"Pharmacological effect of gelsemine on anxiety-like behavior in rat","volume":"253","author":"Meyer","year":"2013","journal-title":"Behav. Brain Res."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1097\/ALN.0b013e31822550f7","article-title":"A single phenylalanine residue in the main intracellular loop of alpha1 gamma-aminobutyric acid type A and glycine receptors influences their sensitivity to propofol","volume":"115","author":"Moraga-Cid","year":"2011","journal-title":"Anesthesiology"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fncel.2012.00001","article-title":"GABA potency at GABA(A) receptors found in synaptic and extrasynaptic zones","volume":"6","author":"Mortensen","year":"2012","journal-title":"Front. Cell. Neurosci."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"S144","DOI":"10.21037\/atm.2019.06.23","article-title":"Cryo-electron microscopy reveals informative details of GABA(A) receptor structural pharmacology: implications for drug discovery","volume":"7","author":"Olsen","year":"2019","journal-title":"Ann. Transl. Med."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/npp.2013.221","article-title":"Antihyperalgesia by \u03b12-GABAA receptors occurs via a genuine spinal action and does not involve supraspinal sites","volume":"39","author":"Paul","year":"2014","journal-title":"Neuropsychopharmacology"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1126\/science.1171870","article-title":"Spinal endocannabinoids and CB1 receptors mediate C-fiber-induced heterosynaptic pain sensitization","volume":"325","author":"Pern\u00eda-Andrade","year":"2009","journal-title":"Science"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"110745","DOI":"10.1016\/j.forsciint.2021.110745","article-title":"Fatal poisoning by accidental ingestion of the \u201cheartbreak grass\u201d (Gelsemium elegans) verified by toxicological and medico-legal analyses","volume":"321","author":"Qu","year":"2021","journal-title":"Forensic Sci. Int."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"6803","DOI":"10.1038\/ncomms7803","article-title":"Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype","volume":"6","author":"Ralvenius","year":"2015","journal-title":"Nat. Commun."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/s0378-8741(03)00267-8","article-title":"Pharmacological effect and toxicity of alkaloids from Gelsemium elegans Benth","volume":"89","author":"Rujjanawate","year":"2003","journal-title":"J. Ethnopharmacol."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"5341","DOI":"10.1007\/s00018-021-03846-2","article-title":"Electrophysiology of ionotropic GABA receptors","volume":"78","author":"Sallard","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"106","DOI":"10.2174\/1874467210801020106","article-title":"Modulation of transmitter release via presynaptic ligand-gated ion channels","volume":"1","author":"Schicker","year":"2008","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.bcp.2019.01.014","article-title":"Gelsemine and koumine, principal active ingredients of Gelsemium, exhibit mechanical antiallodynia via spinal glycine receptor activation-induced allopregnanolone biosynthesis","volume":"161","author":"Shoaib","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/0165-3806(93)90149-5","article-title":"Strychnine-sensitive glycine receptors in cultured primary neurons from rat neocortex","volume":"73","author":"Siebler","year":"1993","journal-title":"Brain Res. Dev. Brain Res."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.eplepsyres.2006.09.008","article-title":"Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery","volume":"73","author":"Taylor","year":"2007","journal-title":"Epilepsy Res."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/j.neuroscience.2008.02.009","article-title":"Regulation of neurosteroid allopregnanolone biosynthesis in the rat spinal cord by glycine and the alkaloidal analogs strychnine and gelsemine","volume":"153","author":"Venard","year":"2008","journal-title":"Neuroscience"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1038\/aps.2015.86","article-title":"Gelsemine alleviates both neuropathic pain and sleep disturbance in partial sciatic nerve ligation mice","volume":"36","author":"Wu","year":"2015","journal-title":"Acta Pharmacol. Sin."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"114546","DOI":"10.1016\/j.jpba.2021.114546","article-title":"Confirmation of Gelsemium elegans poisoning by UHPLC-MS\/MS analysis of koumine, gelsemine, and gelsenicine in hair","volume":"210","author":"Yang","year":"2022","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref39","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":"Biomol. Ther."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"34897","DOI":"10.1074\/jbc.M113.514745","article-title":"Endoplasmic reticulum-associated degradation controls cell surface expression of \u03b3-aminobutyric acid, type B receptors","volume":"288","author":"Zemoura","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"2452","DOI":"10.1016\/j.pain.2013.07.027","article-title":"Gelsemine, a principal alkaloid from Gelsemium sempervirens Ait., exhibits potent and specific antinociception in chronic pain by acting at spinal alpha3 glycine receptors","volume":"154","author":"Zhang","year":"2013","journal-title":"Pain"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.fitote.2014.11.002","article-title":"Gelsemium analgesia and the spinal glycine receptor\/allopregnanolone pathway","volume":"100","author":"Zhang","year":"2015","journal-title":"Fitoterapia"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"204","DOI":"10.3389\/fneur.2017.00204","article-title":"Gelsemium elegans poisoning: a case with 8\u2009months of follow-up and review of the literature","volume":"8","author":"Zhou","year":"2017","journal-title":"Front. 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