Altered desensitization and internalization patterns of rodent versus human glucose-dependent insulinotropic polypeptide (GIP) receptors. An important drug discovery challenge

Lærke Smidt Gasbjerg, Rasmus Syberg Rasmussen, Adrian Dragan, Peter Lindquist, Josefine Ulrikke Melchiorsen, Tomasz Maciej Stepniewski, Sine Schiellerup, Esther Karen Tordrup, Sarina Gadgaard, Hüsün Sheyma Kizilkaya, Sabine Willems, Yi Zhong, Yi Wang, Shane C. Wright, Volker M. Lauschke, Bolette Hartmann, Jens Juul Holst, Jana Selent, Mette Marie Rosenkilde*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Background and Purpose: The gut hormone glucose-dependent insulinotropic polypeptide (GIP) signals via the GIP receptor (GIPR), resulting in postprandial potentiation of glucose-stimulated insulin secretion. The translation of results from rodent studies to human studies has been challenged by the unexpected effects of GIPR-targeting compounds. We, therefore, investigated the variation between species, focusing on GIPR desensitization and the role of the receptor C-terminus. Experimental Approach: The GIPR from humans, mice, rats, pigs, dogs and cats was studied in vitro for cognate ligand affinity, G protein activation (cAMP accumulation), recruitment of beta-arrestin and internalization. Variants of the mouse, rat and human GIPRs with swapped C-terminal tails were studied in parallel. Key Results: The human GIPR is more prone to internalization than rodent GIPRs. Despite similar agonist affinities and potencies for Gαs activation, especially, the mouse GIPR shows reduced receptor desensitization, internalization and beta-arrestin recruitment. Using an enzyme-stabilized, long-acting GIP analogue, the species differences were even more pronounced. ‘Tail-swapped’ human, rat and mouse GIPRs were all fully functional in their Gαs coupling, and the mouse GIPR regained internalization and beta-arrestin 2 recruitment properties with the human tail. The human GIPR lost the ability to recruit beta-arrestin 2 when its own C-terminus was replaced by the rat or mouse tail. Conclusions and Implications: Desensitization of the human GIPR is dependent on the C-terminal tail. The species-dependent functionality of the C-terminal tail and the different species-dependent internalization patterns, especially between human and mouse GIPRs, are important factors influencing the preclinical evaluation of GIPR-targeting therapeutic compounds.

Original languageEnglish
JournalBritish Journal of Pharmacology
ISSN0007-1188
DOIs
Publication statusE-pub ahead of print - 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Keywords

  • class B GPCRs
  • GIP
  • GIP receptor
  • human
  • internalization
  • mouse

Cite this