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Here, we investigate probe\u2010dependent pharmacology in GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptor modulation by integrating molecular dynamics simulations, deep learning\u2010based enhanced sampling, dynamic pharmacophores, and our recently developed MDPath approach for mapping allosteric communication networks. We demonstrate that benzodiazepines and Z\u2010drugs leverage physiological GABA for activity through long\u2010range allosteric coupling. These modulators bind in the transmembrane domain (TMD), establishing allosteric commmunication to the extracellular domain (ECD) GABA binding sites, stabilizing GABA receptor interactions and explaining their probe\u2010dependent positive allosteric modulation. In contrast, anaesthetics forms additional interactions that enable direct binding\u2010driven channel activation independent of GABA, distinguishing ago\u2010PAMs from PAMs despite binding at the same sites. Remarkably, the flumazenil antidote acts by globally disrupting interdomain allosteric communication, selectively preventing the action of ECD\u2010dependent modulators (benzodiazepines and Z\u2010drugs) while sparing anaesthetics' direct effects. Our integrated computational approach reveals the structural determinants of receptor state transitions, providing a framework for understanding probe\u2010dependent pharmacology in ligand\u2010gated ion channels with implications for rational drug design.\n                  <\/jats:p>","DOI":"10.1002\/ardp.70277","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T11:47:00Z","timestamp":1783079220000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Mechanisms and Probe\u2010Dependent Effects of Clinically Relevant GABA\n                    <sub>A<\/sub>\n                    Receptor Modulators"],"prefix":"10.1002","volume":"359","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7988-5068","authenticated-orcid":false,"given":"Marvin","family":"Taterra","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical and Medicinal Chemistry Universit\u00e4t M\u00fcnster M\u00fcnster Germany"},{"name":"GRK 2515, Chemical Biology of Ion Channels (Chembion) Universit\u00e4t M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1060-3353","authenticated-orcid":false,"given":"Yuan","family":"Chang\u2010Halabi","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical and Medicinal Chemistry Universit\u00e4t M\u00fcnster M\u00fcnster Germany"},{"name":"GRK 2515, Chemical Biology of Ion Channels (Chembion) Universit\u00e4t M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7421-3282","authenticated-orcid":false,"given":"Marcel","family":"Berm\u00fadez","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical and Medicinal Chemistry Universit\u00e4t M\u00fcnster M\u00fcnster Germany"},{"name":"GRK 2515, Chemical Biology of Ion Channels (Chembion) Universit\u00e4t M\u00fcnster M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R112.386664"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.2610010103"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0404.2008.01004.x"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.2165\/00023210-200418001-00004"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867003375335"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3181ff72b5"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.5863\/1551-6776-20.5.385"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr215"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ynstr.2020.100212"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08454-1"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06556-w"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13293"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0832-5"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2654-5"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32212-4"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.78.11.7180"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0706251"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2011.01.004"},{"key":"e_1_2_9_20_1","first-page":"2121","article-title":"Addiction: Part I. 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