Fenghui Zhao, Kaini Hang, Qingtong Zhou, Lijun Shao, Hao Li, Wenzhuo Li, Shi Lin, Antao Dai, Xiaoqing Cai, Yanyun Liu, Yingna Xu, Wenbo Feng, Dehua Yang, Ming-Wei Wang
Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor and glucagon receptor in humans to maintain glucose homeostasis. Unlike the other two receptors, GIPR has at least 13 reported splice variants (SVs), more than half of which have sequence variations at either C or N terminus. To explore their roles in endogenous peptide-mediated GIPR signaling, we determined the cryoelectron microscopy (cryo-EM) structures of the two N terminus-altered SVs (referred as GIPR-202 and GIPR-209 in the Ensembl database, SV1 and SV2 here, respectively) and investigated the outcome of coexpressing each of them in question with GIPR in HEK293T cells with respect to ligand binding, receptor expression, cAMP (adenosine 3,5-cyclic monophosphate) accumulation, β-arrestin recruitment, and cell surface localization...
October 10, 2023: Proceedings of the National Academy of Sciences of the United States of America