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However, the physical basis of this modulation is poorly understood. We explore the role of an important gating domain, the \u03b1\n                    <jats:sub>1<\/jats:sub>\n                    M2\u2013M3 linker, in linkage between the BZD site and pore gate. To probe energetics of this coupling without complication from bound agonist, we use a gain of function mutant (\u03b1\n                    <jats:sub>1<\/jats:sub>\n                    L9'T\u03b2\n                    <jats:sub>2<\/jats:sub>\n                    \u03b3\n                    <jats:sub>2L<\/jats:sub>\n                    ) directly activated by BZDs. We identify a specific residue whose mutation (\u03b1\n                    <jats:sub>1<\/jats:sub>\n                    V279A) more than doubles the energetic contribution of the BZD positive modulator diazepam (DZ) to pore opening and also enhances DZ potentiation of GABA-evoked currents in a wild-type background. In contrast, other linker mutations have little effect on DZ efficiency, but generally impair unliganded pore opening. Our observations reveal an important residue regulating BZD-pore linkage, thereby shedding new light on the molecular mechanism of these drugs.\n                  <\/jats:p>","DOI":"10.7554\/elife.64400","type":"journal-article","created":{"date-parts":[[2021,2,16]],"date-time":"2021-02-16T08:02:48Z","timestamp":1613462568000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.64400","source":"Crossref","is-referenced-by-count":20,"title":["A critical residue in the \u03b11M2\u2013M3 linker regulating mammalian GABAA receptor pore gating by diazepam"],"prefix":"10.7554","volume":"10","author":[{"given":"Joseph W","family":"Nors","sequence":"first","affiliation":[{"name":"University of Texas at Austin, Department of Neuroscience, Austin, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shipra","family":"Gupta","sequence":"additional","affiliation":[{"name":"University of Texas at Austin, Department of Neuroscience, Austin, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1466-9808","authenticated-orcid":true,"given":"Marcel P","family":"Goldschen-Ohm","sequence":"additional","affiliation":[{"name":"University of Texas at Austin, Department of Neuroscience, Austin, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2021,2,16]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2018.7399","article-title":"Patterns in outpatient benzodiazepine prescribing in the United States","volume":"2","author":"Agarwal","year":"2019","journal-title":"JAMA Network Open"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1124\/mol.117.110569","article-title":"GABA type A receptor activation in the allosteric coagonist model framework: relationship between EC50 and basal 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