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Molecular interactions of full-length and truncated GIP peptides with the GIP receptor - A comprehensive review
- Source :
- Gabe, M B N, van der Velden, W J C, Smit, F X, Gasbjerg, L S & Rosenkilde, M M 2020, ' Molecular interactions of full-length and truncated GIP peptides with the GIP receptor-A comprehensive review ', Peptides, vol. 125, 170224 . https://doi.org/10.1016/j.peptides.2019.170224
- Publication Year :
- 2019
-
Abstract
- 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.
- Subjects :
- endocrine system
medicine.medical_specialty
Intrinsic activity
DEPENDENT INSULINOTROPIC POLYPEPTIDE
Physiology
Prohormone convertase
Incretin
030209 endocrinology & metabolism
Endogeny
Gastric Inhibitory Polypeptide
Peptide hormone
GIP(1-42)
Biochemistry
Glucagon
GLUCOSE
Receptors, Gastrointestinal Hormone
03 medical and health sciences
Cellular and Molecular Neuroscience
Structure-Activity Relationship
0302 clinical medicine
Endocrinology
GLP-1 RECEPTOR
Internal medicine
medicine
Animals
Humans
chemistry.chemical_classification
GLUCAGON-LIKE PEPTIDE-1
ALANINE SCAN
GIP receptor
Molecular Pharmacology
COMPETITIVE ANTAGONIST
Peptide Fragments
Amino acid
ADIPOSE-TISSUE
chemistry
HIGH-AFFINITY BINDING
HIGH-FAT
GASTRIC-INHIBITORY-POLYPEPTIDE
Antagonists
hormones, hormone substitutes, and hormone antagonists
030217 neurology & neurosurgery
Agonists
Subjects
Details
- ISSN :
- 18735169
- Volume :
- 125
- Database :
- OpenAIRE
- Journal :
- Peptides
- Accession number :
- edsair.doi.dedup.....41f55e5523697b9c8488199e54b4701e