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A Dual GLP-1/GIP Receptor Agonist Does Not Antagonize Glucagon at Its Receptor but May Act as a Biased Agonist at the GLP-1 Receptor.

  • Al-Zamel N Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, PO Box 24923, 13110 Safat, Kuwait.
  • Al-Sabah S Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, PO Box 24923, 13110 Safat, Kuwait. Suleiman@hsc.edu.kw.
  • Luqmani Y Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, PO Box 24923, 13110 Safat, Kuwait.
  • Adi L Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, PO Box 24923, 13110 Safat, Kuwait.
  • Chacko S Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, PO Box 24923, 13110 Safat, Kuwait.
  • Schneider TD Institute of Forensic Medicine, Department of Forensic Pharmacology and Toxicology, University of Zurich, 190/52 CH-8057 Zurich, Switzerland.
  • Krasel C School of Pharmacy, Institute for Pharmacology and Toxicology, The Philipps University of Marburg, Karl-von-Frisch-Straße, 135033 Marburg, Germany.
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  • 2019-07-24
Published in:
  • International journal of molecular sciences. - 2019
GIP
GLP-1
arrestin
glucagon
receptor
Amino Acid Sequence
Arrestin
Bioluminescence Resonance Energy Transfer Techniques
Dose-Response Relationship, Drug
Glucagon
Glucagon-Like Peptide-1 Receptor
HEK293 Cells
Humans
Ligands
Peptides
Receptors, Gastrointestinal Hormone
Receptors, Glucagon
English Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important regulators of metabolism, making their receptors (GLP-1R and GIPR) attractive targets in the treatment of type 2 diabetes mellitus (T2DM). GLP-1R agonists are used clinically to treat T2DM but the use of GIPR agonists remains controversial. Recent studies suggest that simultaneous activation of GLP-1R and GIPR with a single peptide provides superior glycemic control with fewer adverse effects than activation of GLP-1R alone. We investigated the signaling properties of a recently reported dual-incretin receptor agonist (P18). GLP-1R, GIPR, and the closely related glucagon receptor (GCGR) were expressed in HEK-293 cells. Activation of adenylate cyclase via Gαs was monitored using a luciferase-linked reporter gene (CRE-Luc) assay. Arrestin recruitment was monitored using a bioluminescence resonance energy transfer (BRET) assay. GLP-1, GIP, and glucagon displayed exquisite selectivity for their receptors in the CRE-Luc assay. P18 activated GLP-1R with similar potency to GLP-1 and GIPR with higher potency than GIP. Interestingly, P18 was less effective than GLP-1 at recruiting arrestin to GLP-1R and was inactive at GCGR. These data suggest that P18 can act as both a dual-incretin receptor agonist, and as a G protein-biased agonist at GLP-1R.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/271238
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