Molecular interactions of full-length and truncated GIP peptides with the GIP receptor - A comprehensive review
Research output: Contribution to journal › Review › Research › peer-review
Documents
- Molecular interactions of full-length and truncated GIP peptides with the GIP receptor_A comprehensive review_(publisher_version)
Final published version, 1.91 MB, PDF document
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.
Original language | English |
---|---|
Article number | 170224 |
Journal | Peptides |
Volume | 125 |
Number of pages | 8 |
ISSN | 0196-9781 |
DOIs | |
Publication status | Published - 2020 |
- GIP(1-42), GIP receptor, Agonists, Antagonists, DEPENDENT INSULINOTROPIC POLYPEPTIDE, GASTRIC-INHIBITORY-POLYPEPTIDE, GLUCAGON-LIKE PEPTIDE-1, HIGH-AFFINITY BINDING, GLP-1 RECEPTOR, HIGH-FAT, COMPETITIVE ANTAGONIST, ADIPOSE-TISSUE, ALANINE SCAN, GLUCOSE
Research areas
Number of downloads are based on statistics from Google Scholar and www.ku.dk
ID: 248028076