A Photoswitchable Agonist for the Histamine H 3 Receptor, a Prototypic Family A G-Protein-Coupled Receptor

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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 H 3 receptor (hH 3 R). Upon illumination, key compound 65 decreases its affinity for the hH 3 R by 8.5-fold and its potency in hH 3 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 hH 3 R activity. Ligand 65 shows good binding selectivity amongst the histamine receptor subfamily and has good photolytic stability. In all, 65 (VUF15000) is the first photoswitchable GPCR agonist confirmed to be modulated through its affinity and potency upon photoswitching while maintaining its intrinsic activity, rendering it a new chemical biology tool for spatiotemporal control of GPCR activation.

LanguageEnglish
Pages4531-4535
Number of pages5
JournalAngewandte Chemie - International Edition
Volume58
Issue number14
Early online date8 Feb 2019
DOIs
Publication statusPublished - 26 Mar 2019

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Histamine Agonists
G-Protein-Coupled Receptors
Histamine
Proteins
Chemical activation
Ligands
Histamine Receptors
Clamping devices
Isomers
Lighting
Modulation
Electrodes
Electric potential
Experiments

Keywords

  • agonism
  • dynamic modulation
  • H R
  • photopharmacology
  • VUF15000

Cite this

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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 H 3 receptor (hH 3 R). Upon illumination, key compound 65 decreases its affinity for the hH 3 R by 8.5-fold and its potency in hH 3 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 hH 3 R activity. Ligand 65 shows good binding selectivity amongst the histamine receptor subfamily and has good photolytic stability. In all, 65 (VUF15000) is the first photoswitchable GPCR agonist confirmed to be modulated through its affinity and potency upon photoswitching while maintaining its intrinsic activity, rendering it a new chemical biology tool for spatiotemporal control of GPCR activation.",
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author = "Hauwert, {Niels J.} and Mocking, {Tamara A.M.} and {Da Costa Pereira}, Daniel and Ken Lion and Yara Huppelschoten and Vischer, {Henry F.} and {De Esch}, {Iwan J.P.} and Maikel Wijtmans and Rob Leurs",
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AU - Lion, Ken

AU - Huppelschoten, Yara

AU - Vischer, Henry F.

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AU - Leurs, Rob

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