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Adv."],"published-print":{"date-parts":[[2026,7,31]]},"abstract":"<jats:p>\n                    \u03b3-Aminobutyric acid type-A (GABA\n                    <jats:sub>A<\/jats:sub>\n                    ) receptors are the principal mediators of inhibitory neurotransmission in the human central nervous system. The \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    - and \u03b1\n                    <jats:sub>3<\/jats:sub>\n                    -containing subtypes have tightly controlled spatial expression profiles, which influence anxiety, nociception, epilepsy, and autism. \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    \/\u03b1\n                    <jats:sub>3<\/jats:sub>\n                    -Selective small molecules compromise on strength of effect (efficacy) to avoid off-subtype modulation. To break this pharmacological deadlock, we study here a panel of nanobodies (NBs) raised against \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    - and \u03b1\n                    <jats:sub>3<\/jats:sub>\n                    -containing GABA\n                    <jats:sub>A<\/jats:sub>\n                    receptors. We identify subtype selective silent binders, positive allosteric modulators (PAMs), and inhibitors. Cryo\u2013electron microscopy structures explain the binding modes and molecular mechanisms of action of representative NBs. Modulators exhibit distinct synaptic and extrasynaptic functional profiles in brain slices and neuronal networks and can reduce anxiety in vivo. These selective and efficacious NBs (whether inhibitors or positive modulators) enable strong yet precise pharmacological control of \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    \/\u03b1\n                    <jats:sub>3<\/jats:sub>\n                    -containing subtypes to advance basic research and as potential therapeutic leads to treat neuropsychiatric disorders.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeg3548","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T17:59:11Z","timestamp":1785347951000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Determining the molecular and physiological actions of subtype-selective nanobodies of GABA\n                    <sub>A<\/sub>\n                    receptors"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2998-1989","authenticated-orcid":true,"given":"Jose Enrique","family":"Gonzalez-Prada","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Cambridge, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6776-2216","authenticated-orcid":true,"given":"Sulin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Cambridge, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuhan","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Cambridge, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2131-0740","authenticated-orcid":true,"given":"Chloe S.","family":"Chernoff","sequence":"additional","affiliation":[{"name":"Department of Psychology, University of Cambridge, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9130-2677","authenticated-orcid":true,"given":"Damian P.","family":"Bright","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5873-7107","authenticated-orcid":true,"given":"Martin","family":"Mortensen","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte F.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Cambridge, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2712-6817","authenticated-orcid":true,"given":"Stephanie","family":"Nestorow","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Cambridge, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1241-4038","authenticated-orcid":true,"given":"Vikram Babu","family":"Kasaragod","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Cambridge, Cambridge, UK."},{"name":"MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Na","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Cambridge, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4594-0808","authenticated-orcid":true,"given":"Saad","family":"Hannan","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK."},{"name":"Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1211-6885","authenticated-orcid":true,"given":"Jianchong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Cambridge, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1504-499X","authenticated-orcid":true,"given":"Alexander W. 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