Pharmacological characterization of seven human histamine H3 receptor isoforms

Meichun Gao, Mabel E. Dekker, Rob Leurs, Henry F. Vischer

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The histamine H3 receptor (H3R) regulates as a presynaptic G protein-coupled receptor the release of histamine and other neurotransmitters in the brain, and is consequently a potential therapeutic target for neuronal disorders. The human H3R encodes for seven splice variants that vary in the length of intracellular loop 3 and/or the C-terminal tail but are all able to induce heterotrimeric Gi protein signaling. The last two decades H3R drug discovery and lead optimization has been exclusively focused on the 445 amino acids-long reference isoform H3R-445. In this study, we pharmacologically characterized for the first time all seven H3R isoforms by determining their binding affinities for reference histamine H3 receptor agonists and inverse agonists. The H3R-453, H3R-415, and H3R-413 isoforms display similar binding affinities for all ligands as the H3R-445. However, increased agonist binding affinities were observed for the three shorter isoforms H3R-329, H3R-365, and H3R-373, whereas inverse agonists such as the approved anti-narcolepsy drug pitolisant (Wakix®) displayed significantly decreased binding affinities for the latter two isoforms. This opposite change in binding affinity of agonist versus inverse agonists on H3R-365 and H3R-373 is associated with their higher constitutive activity in a cAMP biosensor assay as compared to the other five isoforms. The observed differences in pharmacology between longer and shorter H3R isoforms should be considered in future drug discovery programs.

Original languageEnglish
Article number176450
Pages (from-to)1-12
Number of pages12
JournalEuropean Journal of Pharmacology
Volume968
Early online date21 Feb 2024
DOIs
Publication statusPublished - 5 Apr 2024

Bibliographical note

Publisher Copyright:
Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.

Funding

Meichun Gao is supported by CSC Chinese scholarship grant [ 202006310027 ]. We thank Dr. Mirjam Zimmermann for providing the HEK293-EPAC cells.

FundersFunder number
China Scholarship Council202006310027

    Keywords

    • Binding selectivity
    • Constitutive activity
    • Efficacy
    • GPCR
    • Histamine H(3) receptor
    • Isoforms

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