{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T06:15:17Z","timestamp":1778652917151,"version":"3.51.4"},"reference-count":87,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"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>\n                    Anxiety disorders are associated with impaired inhibitory neurotransmission mediated by \u03b3-aminobutyric acid type A (GABA-A) receptors. Although benzodiazepines remain effective anxiolytics, their clinical utility is limited by sedation, cognitive impairment, tolerance, and dependence, prompting the search for mechanistically distinct GABAergic modulators. Among cannabinoid-related molecules, the strongest evidence for direct GABA-A receptor modulation concerns the endocannabinoid 2-arachidonoylglycerol (2-AG), which potentiates recombinant human \u03b1\n                    <jats:sub>1<\/jats:sub>\n                    \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    \u03b3\n                    <jats:sub>2<\/jats:sub>\n                    receptors through residues located in the M4 helix of the \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    subunit. Here, we review the structural architecture, biophysical properties, and pharmacological profile of the human GABA-A \u03b1\n                    <jats:sub>1<\/jats:sub>\n                    \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    \u03b3\n                    <jats:sub>2<\/jats:sub>\n                    isoform as the relevant molecular framework for evaluating this mechanism, while discussing the broader relevance of cannabinoid-related ligands and selected phytocannabinoids without assuming mechanistic equivalence. We further assess the hypothesis that 2-AG reaches the \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -M4 site through a membrane-access route and identify five conceptual barriers that currently limit translation of this mechanism into anxiolytic drug development: supraphysiological effective concentrations, unresolved synaptic-versus-extrasynaptic actions, uncertain subtype selectivity, incomplete validation of lipid-environment effects, and lack of clinical evidence linking this mechanism to anxiolysis in humans. We conclude that direct modulation through \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -M4 defines a mechanistically intriguing allosteric pathway distinct from benzodiazepine action; however, its location on a shared \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    subunit and the micromolar concentrations required for modulation represent substantial obstacles to the rational design of anxioselective agents based on this mechanism.\n                  <\/jats:p>","DOI":"10.3389\/fnins.2026.1813618","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T05:53:45Z","timestamp":1778651625000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Direct modulation of human GABA-A \u03b11\u03b22\u03b32 receptors by the endocannabinoid 2-arachidonoylglycerol: implications for cannabinoid-related ligands and limitations for anxiolytic drug development"],"prefix":"10.3389","volume":"20","author":[{"given":"Edgar","family":"Mixcoha","sequence":"first","affiliation":[{"name":"Secretar\u00eda de Ciencia Humanidades Tecnolog\u00eda e Innovaci\u00f3n - Instituto Nacional de Medicina Gen\u00f3mica","place":["Mexico City, Mexico"]},{"name":"Facultad de Ciencias de la Salud, Universidad An\u00e1huac","place":["Mexico City, Mexico"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anabel","family":"Flores-Zamora","sequence":"additional","affiliation":[{"name":"Instituto Nacional de Psiquiatr\u00eda Ram\u00f3n de la Fuente Mu\u00f1iz (INPRFM)","place":["Mexico City, Mexico"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ricardo","family":"Hern\u00e1ndez-Miramontes","sequence":"additional","affiliation":[{"name":"Instituto Nacional de Psiquiatr\u00eda Ram\u00f3n de la Fuente Mu\u00f1iz (INPRFM)","place":["Mexico City, Mexico"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge Alberto","family":"Hern\u00e1ndez-Calder\u00f3n","sequence":"additional","affiliation":[{"name":"Instituto Nacional de Psiquiatr\u00eda Ram\u00f3n de la Fuente Mu\u00f1iz (INPRFM)","place":["Mexico City, Mexico"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susana","family":"Marti\u00f1\u00f3n","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias de la Salud, Universidad An\u00e1huac","place":["Mexico City, Mexico"]},{"name":"Instituto Nacional de Psiquiatr\u00eda Ram\u00f3n de la Fuente Mu\u00f1iz (INPRFM)","place":["Mexico City, Mexico"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"ref1","first-page":"331","volume-title":"Behavioral Neurobiology of Anxiety and its Treatment","author":"Atack","year":"2010"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.phrs.2017.02.022","article-title":"The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptors","volume":"119","author":"Bakas","year":"2017","journal-title":"Pharmacol. 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