A Photoswitchable Agonist for the Histamine H₃ Receptor, a Prototypic Family A G-Protein-Coupled Receptor.

ABSTRACT: Spatiotemporal control over biochemical signaling processes involving G protein-coupled receptors (GPCRs) is highly desired for dissecting their complex intracellular signaling. We developed sixteen photoswitchable ligands for the human histamine H₃ receptor (hH₃ R). Upon illumination, key compound 65 decreases its affinity for the hH₃ R by 8.5-fold and its potency in hH₃ R-mediated G_i protein activation by over 20-fold, with the trans and cis isomer both acting as full agonist. In real-time two-electrode voltage clamp experiments in Xenopus oocytes, 65 shows rapid light-induced modulation of hH₃ R activity. Ligand 65 shows good binding selectivity amongst the histamine receptor subfamily and has good photolytic stability. I

SUBMITTER: Hauwert NJ 

PROVIDER: S-EPMC6563694 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature