Molecular interactions of full-length and truncated GIP peptides with the GIP receptor – A comprehensive review

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2020-03, Vol.125, p.170224-170224, Article 170224
• Main Authors: Gabe, Maria Buur Nordskov, van der Velden, Wijnand J.C., Smit, Florent Xavier, Gasbjerg, Lærke Smidt, Rosenkilde, Mette Marie
• Format: Article
• Language: English
• Subjects: Agonists; Animals; Antagonists; Gastric Inhibitory Polypeptide - chemistry; Gastric Inhibitory Polypeptide - metabolism; GIP receptor; GIP(1-42); Humans; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Receptors, Gastrointestinal Hormone - chemistry; Receptors, Gastrointestinal Hormone - metabolism; Structure-Activity Relationship
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2019.170224

•The N-terminus of GIP is essential for receptor activation.•The C-terminus of GIP has no apparent interaction with the GIP receptor.•C-terminal modifications of GIP has a minimal effect on receptor activation.•The absence of the c-terminus of GIP improves the antagonistic action for the GIP receptor. Enzymatic cleavage of endogenous peptides is a commonly used principle to initiate, modulate and terminate action for instance among cytokines and peptide hormones. The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and the related hormone glucagon-like peptide-2 (GLP-2) are all rapidly N-terminally truncated with severe loss of intrinsic activity. The most abundant circulating form of full length GIP(1–42) is GIP(3–42) (a dipeptidyl peptidase-4 (DPP-4) product). GIP(1–30)NH2 is another active form resulting from prohormone convertase 2 (PC2) cleavage of proGIP. Like GIP(1–42), GIP(1–30)NH2 is a substrate for DPP-4 generating GIP(3–30)NH2 which, compared to GIP(3–42), binds with higher affinity and very efficiently inhibits GIP receptor (GIPR) activity with no intrinsic activity. Here, we review the action of these four and multiple other N- and C-terminally truncated forms of GIP with an emphasis on molecular pharmacology, i.e. ligand binding, subsequent receptor activation and desensitization. Our overall conclusion is that the N-terminus is essential for receptor activation as GIP N-terminal truncation leads to decreased/lost intrinsic activity and antagonism (similar to GLP-1 and GLP-2), whereas the C-terminal extension of GIP(1–42), as compared to GLP-1, GLP-2 and glucagon (29–33 amino acids), has no apparent impact on the GIPR in vitro, but may play a role for other properties such as stability and tissue distribution. A deeper understanding of the molecular interaction of naturally occurring and designed GIP-based peptides, and their impact in vivo, may contribute to a future therapeutic targeting of the GIP system – either with agonists or with antagonists, or both.