Jul 30, 2016

BRET-based β-arrestin2 recruitment to the histamine H1 receptor for investigating antihistamine binding kinetics

Pharmacological Research : the Official Journal of the Italian Pharmacological Society
Reggie BosmaHenry F Vischer


Ligand residence time is thought to be a critical parameter for optimizing the in vivo efficacy of drug candidates. For the histamine H1 receptor (H1R) and other G protein-coupled receptors, the kinetics of ligand binding are typically measured by low throughput radioligand binding experiments using homogenized cell membranes expressing the target receptor. In this study, a real-time proximity assay between H1R and β-arrestin2 in living cells was established to investigate the dynamics of antihistamine binding to the H1R. No receptor reserve was found for the histamine-induced recruitment of β-arrestin2 to the H1R and the transiently recruited β-arrestin2 therefore reflected occupancy of the receptor by histamine. Antihistamines displayed similar kinetic signatures on antagonizing histamine-induced β-arrestin2 recruitment as compared to displacing radioligand binding from the H1R. This homogeneous functional method unambiguously determined the fifty-fold difference in the dissociation rate constant between mepyramine and the long residence time antihistamines levocetirizine and desloratadine.

Mentioned in this Paper

Histamine Measurement
In Vivo
Receptors, Histamine H1
HEK293 Cells
Bioluminescence Resonance Energy Transfer Techniques
Ligand Binding

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