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

Gasbjerg, Lærke Smidt; Rasmussen, Rasmus Syberg; Dragan, Adrian; Lindquist, Peter; Melchiorsen, Josefine Ulrikke; Stepniewski, Tomasz Maciej, 1988-; Schiellerup, Sine; Tordrup, Esther Karen; Gadgaard, Sarina; Kizilkaya, Hüsün Sheyma; Willems, Sabine; Zhong, Yi; Wang, Yi; Wright, Shane C.; Lauschke, Volker M.; Hartmann, Bolette; Holst, Jens Juul; Selent, Jana; Rosenkilde, Mette Marie

doi:http://dx.doi.org/10.1111/bph.16478

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

Citació

Gasbjerg LS, Rasmussen RS, Dragan A, Lindquist P, Melchiorsen JU, Stepniewski TM, Schiellerup S, Tordrup EK, Gadgaard S, Kizilkaya HS, Willems S, Zhong Y, Wang Y, Wright SC, Lauschke VM, Hartmann B, Holst JJ, Selent J, Rosenkilde MM. Altered desensitization and internalization patterns of rodent versus human glucose-dependent insulinotropic polypeptide (GIP) receptors. An important drug discovery challenge. Br J Pharmacol. 2025 Jul;182(14):3353-70. DOI: 10.1111/bph.16478

Resum

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. Linked articles: This article is part of a themed issue Complexity of GPCR Modulation and Signaling (ERNST). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.14/issuetoc.