A propofol binding site on mammalian GABAA receptors identified by photolabeling
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Propofol is the most important intravenous general anesthetic in current clinical use. It acts by potentiating GABAA (γ-aminobutyric acid type A) receptors, but where it binds to this receptor is not known and has been a matter of some debate. We synthesized a new propofol analog photolabeling reagent whose biological activity is very similar to that of propofol. We confirmed that this reagent labeled known propofol binding sites in human serum albumin that have been identified using X-ray crystallography. Using a combination of protiated and deuterated versions of the reagent to label mammalian receptors in intact membranes, we identified a new binding site for propofol in GABAA receptors consisting of both β3 homopentamers and α1β3 heteropentamers. The binding site is located within the β subunit at the interface between the transmembrane domains and the extracellular domain and lies close to known determinants of anesthetic sensitivity in the transmembrane segments TM1 and TM2.
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Anesthetic drugs bind directly to GABAA receptors, as shown by X-ray crystallography and high-resolution mass spectrometry.
“direct evidence of anesthetic drugs binding to GABAA receptors has been demonstrated both with X-ray crystallographic and high resolution mass spectrometry studies [35–37].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [36]
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- Authors
- Yip, G. M. S., Chen, Z.-W., Edge, C. J., Smith, E. H., Dickinson, R., Hohenester, E., Townsend, R. R., Fuchs, K., Sieghart, W., Evers, A. S., & Franks, N. P.
- Affiliations
- Imperial College London (GB)
- Washington University in St. Louis (US)
- Royal Berkshire Hospital (GB)
- Medical University of Vienna (AT)
- Corresponding author
- Evers, Alex S
- Franks, Nicholas P
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2013-09-22
- Volume
- 9
- Issue
- 11
- Pages
- 715-720
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC3951778
- OpenAlex
- W1972473633
- Cited by
- 226
- References
- 40
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 9 · 2023: 7 · 2022: 12 · 2021: 19 · 2020: 19 · 2019: 21 · 2018: 30 · 2017: 20 · 2016: 31 · 2015: 18 · 2014: 22 · 2013: 5
- FWCI
- 12.43
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- National Institutes of Health (5p41rr000954-34)
- National Institute of General Medical Sciences (P01GM047969, P01GM47969, P41GM103422)
- National Center for Research Resources (P41-RR000954, UL1RR024992)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- propofol, GABAA receptor, anesthetic binding sites, beta subunit, transmembrane domain, extracellular domain, anesthetic sensitivity, general anesthetics, human serum albumin
- MeSH terms
- Binding Sites, Humans, Models, Molecular, Receptors, GABA-A, Serum Albumin, Structure-Activity Relationship, Molecular Structure, Propofol, Photoaffinity Labels
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