{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T01:28:03Z","timestamp":1775698083925,"version":"3.50.1"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background:<\/jats:title><jats:p>The \u03b3-aminobutyric acid (GABA) type A receptor is a target for several anesthetics, anticonvulsants, anxiolytics, and sedatives. Neurosteroids, barbiturates, and etomidate both potentiate responses to GABA and allosterically activate the receptor. We examined the ability of a benzodiazepine, diazepam, to potentiate responses to allosteric agonists.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>The GABA type A receptors were expressed in human embryonic kidney 293 cells and studied using whole-cell and single-channel patch clamp. The receptors were activated by the orthosteric agonist GABA and allosteric agonists pentobarbital, etomidate, and alfaxalone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>Diazepam is equally potent at enhancing responses to orthosteric and allosteric agonists. Diazepam EC<jats:sub>50<\/jats:sub>s were 25 \u00b1 4, 26 \u00b1 6, 33 \u00b1 6, and 26 \u00b1 3 nm for receptors activated by GABA, pentobarbital, etomidate, and alfaxalone, respectively (mean \u00b1 SD, 5\u20136 cells at each condition). Mutations to the benzodiazepine-binding site (\u03b11(H101C), \u03b32(R144C), \u03b32(R197C)) reduced or removed potentiation for all agonists, and an inverse agonist at the benzodiazepine site reduced responses to all agonists. Single-channel data elicited by GABA demonstrate that in the presence of 1 \u03bcm diazepam the prevalence of the longest open-time component is increased from 13 \u00b1 7 (mean \u00b1 SD, n = 5 patches) to 27 \u00b1 8% (n = 3 patches) and the rate of channel closing is decreased from 129 \u00b1 28 s<jats:sup>\u22121<\/jats:sup>to 47 \u00b1 6 s<jats:sup>\u22121<\/jats:sup>(mean\u00b1SD)<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions:<\/jats:title><jats:p>We conclude that benzodiazepines do not act by enhancing affinity of the orthosteric site for GABA but rather by increasing channel gating efficacy. The results also demonstrate the presence of interactions between allosteric activators and potentiators, raising a possibility of effects on dosage requirements or changes in side effects.<\/jats:p><\/jats:sec>","DOI":"10.1097\/aln.0b013e318289bcd3","type":"journal-article","created":{"date-parts":[[2013,2,12]],"date-time":"2013-02-12T12:05:18Z","timestamp":1360670718000},"page":"1417-1425","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":33,"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"],"prefix":"10.1097","volume":"118","author":[{"given":"Ping","family":"Li","sequence":"first","affiliation":[{"name":"Senior Scientist"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan M.","family":"Eaton","sequence":"additional","affiliation":[{"name":"Senior Research 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