Modulation of α1β3γ2 GABA <sub>A</sub> receptors expressed in <i>X. laevis</i> oocytes using a propofol photoswitch tethered to the transmembrane helix
Cecilia M. Borghese, Hua‐Yu Leo Wang, Stanton F. McHardy, Robert O. Messing, James R. Trudell, R. Adron Harris, Edward Bertaccini
Abstract
Significance Mechanisms of anesthesia remain obscure. We developed a β-subunit-specific tethered photoswitch containing the widely used anesthetic, propofol, to study the anesthetic mechanisms through γ-aminobutyric acid type A (GABA A ) receptors critical for this drug’s effects. Photoswitches are molecules that shift between two isomeric forms after irradiation with light at a specific wavelength, which would produce different biological outcomes on their targets. Tethered photoswitches possess reactive groups that can covalently bind to their target. We identified several residues in the receptor transmembrane domains that are suitable for tethering. Once bound and after photoirradiation, the propofol moiety of MAP20 swings into its binding site, allowing for light-controlled potentiation of the GABA A receptor expressed in Xenopus laevis oocytes.