Insights into agonist-elicited activation of the human glucose-dependent insulinotropic polypeptide receptor

Elita Yuliantie, Wijnand J C van der Velden, Viktorija Labroska, Antao Dai, Fenghui Zhao, Sanaz Darbalaei, Giuseppe Deganutti, Tongyang Xu, Qingtong Zhou, Dehua Yang, Mette M Rosenkilde, Patrick M Sexton, Ming-Wei Wang, Denise Wootten

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Glucose-dependent insulinotropic polypeptide (GIP) and its receptor (GIPR) are part of the incretin system that regulates glucose homeostasis. A series of GIPR residues putatively important for ligand binding and receptor activation were mutated and pharmacologically evaluated using GIPR selective agonists in cAMP accumulation, ERK1/2 phosphorylation (pERK1/2) and β-arrestin 2 recruitment assays. The impact of mutation on ligand efficacy was determined by operational modelling of experimental data for each mutant, with results mapped onto the full-length, active-state GIPR structure. Two interaction networks, comprising transmembrane helix (TM) 7, TM1 and TM2, and extracellular loop (ECL) 2, TM5 and ECL3 were revealed, respectively. Both networks were critical for Gα s-mediated cAMP accumulation and the recruitment of β-arrestin 2, however, cAMP response was more sensitive to alanine substitution, with most mutated residues displaying reduced signaling. Unlike the other two assays, activation of ERK1/2 was largely independent of the network involving ECL2, TM5 and ECL3, indicating that pERK1/2 is at least partially distinct from Gα s or β-arrestin pathways and this network is also crucial for potential biased agonism at GIPR. Collectively, our work advances understanding of the structure–function relationship of GIPR and provides a framework for the design and/or interpretation of GIP analogues with unique signaling profiles.

Original languageEnglish
Article number114715
Number of pages16
JournalBiochemical Pharmacology
Early online date30 Jul 2021
Publication statusPublished - Oct 2021

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  • Glucose-dependent insulinotropic polypeptide receptor
  • G protein-coupled receptor
  • GPCR structure–function relationship
  • ERK
  • cAMP
  • Arrestin

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology


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