A propofol binding site on mammalian GABA A receptors identified by photolabeling

Grace M.S. Yip, Zi Wei Chen, Christopher J. Edge, Edward H. Smith, Robert Dickinson, Erhard Hohenester, R. Reid Townsend, Karoline Fuchs, Werner Sieghart, Alex S. Evers, Nicholas P. Franks

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135 Scopus citations

Abstract

Propofol is the most important intravenous general anesthetic in current clinical use. It acts by potentiating GABA A (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 GABA A receptors consisting of both β 3 homopentamers and α 1 β 3 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.

Original languageEnglish
Pages (from-to)715-720
Number of pages6
JournalNature Chemical Biology
Volume9
Issue number11
DOIs
StatePublished - Nov 1 2013

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    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. (2013). A propofol binding site on mammalian GABA A receptors identified by photolabeling. Nature Chemical Biology, 9(11), 715-720. https://doi.org/10.1038/nchembio.1340