{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T03:54:12Z","timestamp":1790481252784,"version":"4.1.0"},"reference-count":226,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T00:00:00Z","timestamp":1610582400000},"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. Neurosci."],"abstract":"<jats:p>Diverse populations of GABA<jats:sub>A<\/jats:sub> receptors (GABA<jats:sub>A<\/jats:sub>Rs) throughout the brain mediate fast inhibitory transmission and are modulated by various endogenous ligands and therapeutic drugs. Deficits in GABA<jats:sub>A<\/jats:sub>R signaling underlie the pathophysiology behind neurological and neuropsychiatric disorders such as epilepsy, anxiety, and depression. Pharmacological intervention for these disorders relies on several drug classes that target GABA<jats:sub>A<\/jats:sub>Rs, such as benzodiazepines and more recently neurosteroids. It has been widely demonstrated that subunit composition and receptor stoichiometry impact the biophysical and pharmacological properties of GABA<jats:sub>A<\/jats:sub>Rs. However, current GABA<jats:sub>A<\/jats:sub>R-targeting drugs have limited subunit selectivity and produce their therapeutic effects concomitantly with undesired side effects. Therefore, there is still a need to develop more selective GABA<jats:sub>A<\/jats:sub>R pharmaceuticals, as well as evaluate the potential for developing next-generation drugs that can target accessory proteins associated with native GABA<jats:sub>A<\/jats:sub>Rs. In this review, we briefly discuss the effects of benzodiazepines and neurosteroids on GABA<jats:sub>A<\/jats:sub>Rs, their use as therapeutics, and some of the pitfalls associated with their adverse side effects. We also discuss recent advances toward understanding the structure, function, and pharmacology of GABA<jats:sub>A<\/jats:sub>Rs with a focus on benzodiazepines and neurosteroids, as well as newly identified transmembrane proteins that modulate GABA<jats:sub>A<\/jats:sub>Rs.<\/jats:p>","DOI":"10.3389\/fnins.2020.616298","type":"journal-article","created":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T18:56:44Z","timestamp":1610650604000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":53,"title":["Looking for Novelty in an \u201cOld\u201d Receptor: Recent Advances Toward Our Understanding of GABAARs and Their Implications in Receptor Pharmacology"],"prefix":"10.3389","volume":"14","author":[{"given":"David","family":"Castellano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan David","family":"Shepard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7132","DOI":"10.1073\/pnas.1403285111","article-title":"Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors.","volume":"111","author":"Abramian","year":"2014","journal-title":"Proc. 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