Abstract Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) in humans to maintain glucose homeostasis. Unlike the other two receptors, GIPR has at least 7 reported (EMBL-EBI, 2022; NCBI, 2022a, 2022b) splice variants (SVs) with previously undefined functions. To explore their roles in endogenous peptide mediated GIPR signaling, we investigated the outcome of co-expressing each of the four SVs in question with GIPR in terms of ligand binding, cAMP accumulation, G s activation, β-arrestin recruitment and cell surface localization. The effects of these SVs on intracellular cAMP responses modulated by receptor activity-modifying proteins (RAMPs) were also studied. It was found that while SVs of GIPR neither bound to the hormone nor affected its signal transduction per se , they differentially regulated GIPR-mediated cAMP and β-arrestin responses. Specifically, SV1 and SV4 were preferable to G s signaling, SV3 was biased towards β-arrestin recruitment, whereas SV2 was inactive on both pathways. In the presence of RAMPs, only SV1 and SV4 synergized the repressive action of RAMP3 on GIP-elicited cAMP production. The results suggest a new form of signal bias that is constitutive and ligand-independent, thereby expanding our knowledge of biased signaling beyond pharmacological manipulation ( i . e ., ligand specific) as well as constitutive and ligand-dependent ( e . g ., SV1 of the growth hormone-releasing hormone receptor).

Ligand-independent modulation of GIPR signaling by splice variants