Dataset Information

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 Gi 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. 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.

SUBMITTER: Hauwert NJ

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

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Hauwert Niels J NJ Mocking Tamara A M TAM Da Costa Pereira Daniel D Lion Ken K Huppelschoten Yara Y Vischer Henry F HF De Esch Iwan J P IJP Wijtmans Maikel M Leurs Rob R

Angewandte Chemie (International ed. in English) 20190227 14

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 Gi protein activation by over 20-fold, with the trans and c ...[more]

PMID: 30735597

Similar Datasets

Project description:Hemorrhagic shock has a potential to be life-threatening when it is not treated. The main causes of hemorrhagic shock involve: (1) forces causing injury; and (2) diseases that can cause hemorrhage., Therefore, due to the causes of hemorrhagic shock and the life-threatening potential, the search for new methods of shock treatment is extremely valuable to the modern medicine. The aim of this study was to investigate the influence of clobenpropit in the model of hemorrhagic shock. The experiments were conducted in 110 adult male Wistar rats weighing between 205 and 470g. 1, 2 and 5 ?mol/kg of intravenous H3 receptors reverse agonists, clobentropit, and/or 1, 5 and 10 ?mol/kg H3 receptor agonist, imetit, were used as general anesthetics. Irreversible hemorrhagic shock was induced by the paused bleeding until the mean arterial pressure (MAP) lowered to the level of 20-25 mmHg. It was proved that, in cases of critical hypotension, clobenpropit triggered a dose-dependent increase of: systolic blood pressure (SBP), diastolic blood pressure (DBP), MPA and heart rate (HR) of rats with critical hypotension. The most significant changes in hemodynamic parameters were achieved by administrating dosages of 2 mmol/kg. This resulted in the survival rate increase to up to 100%. However, imetit did not trigger any hemodynamic changes nor an increase in SBP, DBP, MAP or HR. Furthermore, it was found that the premedication with prazosin, yohimbine, 6-hydroxydopamine and the vasopressin V1a receptor antagonist blocked the effects of clobenpropit. Additionally, premedication with propranolol, captopril and ZD 7155 did not cause any significant changes in the measured hemodynamic parameters. In conclusion, after an intravenous injection clobenpropit, the inverse agonist of H3 histamine receptors/agonist of histamine receptors H4, causes a resuscitating effect on rats in hemorrhagic shock. Moreover, such effect is based on the effector mechanisms of sympathetic nervous system and vasopressin.

Dataset Information

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

Publications

A Photoswitchable Agonist for the Histamine H<sub>3</sub> Receptor, a Prototypic Family A G-Protein-Coupled Receptor.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets