Molecular interactions of full-length and truncated GIP peptides with the GIP receptor - A comprehensive review
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Molecular interactions of full-length and truncated GIP peptides with the GIP receptor - A comprehensive review. / Gabe, Maria Buur Nordskov; van der Velden, Wijnand J. C.; Smit, Florent Xavier; Gasbjerg, Laerke Smidt; Rosenkilde, Mette Marie.
In: Peptides, Vol. 125, 170224, 2020.Research output: Contribution to journal › Review › Research › peer-review
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TY - JOUR
T1 - Molecular interactions of full-length and truncated GIP peptides with the GIP receptor - A comprehensive review
AU - Gabe, Maria Buur Nordskov
AU - van der Velden, Wijnand J. C.
AU - Smit, Florent Xavier
AU - Gasbjerg, Laerke Smidt
AU - Rosenkilde, Mette Marie
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - GIP(1-42)
KW - GIP receptor
KW - Agonists
KW - Antagonists
KW - DEPENDENT INSULINOTROPIC POLYPEPTIDE
KW - GASTRIC-INHIBITORY-POLYPEPTIDE
KW - GLUCAGON-LIKE PEPTIDE-1
KW - HIGH-AFFINITY BINDING
KW - GLP-1 RECEPTOR
KW - HIGH-FAT
KW - COMPETITIVE ANTAGONIST
KW - ADIPOSE-TISSUE
KW - ALANINE SCAN
KW - GLUCOSE
U2 - 10.1016/j.peptides.2019.170224
DO - 10.1016/j.peptides.2019.170224
M3 - Review
C2 - 31809770
VL - 125
JO - Peptides
JF - Peptides
SN - 0196-9781
M1 - 170224
ER -
ID: 248028076