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Tethered photoswitches are molecules with two photo-dependent isomeric forms, each with different actions on their biological targets. They include reactive chemical groups capable of covalently binding to their target. Our aim was to develop a β-subunit-tethered propofol photoswitch (MAP20), as a tool to better study the mechanism of anesthesia through the GABA A α1β3γ2 receptor. We used short spacers between the tether (methanethiosulfonate), the photosensitive moiety (azobenzene), and the ligand (propofol), to allow a precise tethering adjacent to the putative propofol binding site at the β + α - interface of the receptor transmembrane helices (TMs). First, we used molecular modeling to identify possible tethering sites in β3TM3 and α1TM1, and then introduced cysteines in the candidate positions. Two mutant subunits [β3(M283C) and α1(V227C)] showed photomodulation of GABA responses after incubation with MAP20 and illumination with lights at specific wavelengths. The α1β3(M283C)γ2 receptor showed the greatest photomodulation, which decreased as GABA concentration increased. The location of the mutations that produced photomodulation confirmed that the propofol binding site is located in the β + α - interface close to the extracellular side of the transmembrane helices. Tethering the photoswitch to cysteines introduced in the positions homologous to β3M283 in two other subunits (α1W288 and γ2L298) also produced photomodulation, which was not entirely reversible, probably reflecting the different nature of each interface. The results are in agreement with a binding site in the β + α - interface for the anesthetic propofol.

proceedings of the national academy of sciences of the united states of america

Modulation of α1β3γ2 GABA <sub>A</sub> receptors expressed in <i>X. laevis</i> oocytes using a propofol photoswitch tethered to the transmembrane helix

Modulation of α1β3γ2 GABA A receptors expressed in X. laevis oocytes using a propofol photoswitch tethered to the transmembrane helix

Modulation of α1β3γ2 GABA _A receptors expressed in X. laevis oocytes using a propofol photoswitch tethered to the transmembrane helix