PT  - JOURNAL ARTICLE
AU  - Cassandra Koole
AU  - Denise Wootten
AU  - John Simms
AU  - Celine Valant
AU  - Rohan Sridhar
AU  - Owen L Woodman
AU  - Laurence J Miller
AU  - Roger J. Summers
AU  - Arthur Christopoulos
AU  - Patrick Sexton
TI  - Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner; implications for drug screening
AID  - 10.1124/mol.110.065664
DP  - 2010 Jun 14
TA  - Molecular Pharmacology
PG  - mol.110.065664
4099  - http://molpharm.aspetjournals.org/content/early/2010/06/14/mol.110.065664.short
4100  - http://molpharm.aspetjournals.org/content/early/2010/06/14/mol.110.065664.full
AB  - The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of insulin secretion and a major therapeutic target for treatment of diabetes. However, GLP-1 receptor function is complex with multiple endogenous peptides that can interact with the receptor, including full length (1-37) and truncated (7-37) forms of GLP-1 that can each exist in an amidated form, and the related peptide oxyntomodulin. We have investigated two GLP-1 receptor allosteric modulators, Novo Nordisk compound 2 and quercetin, and their ability to modify binding and signalling (cAMP formation, intracellular Ca2+ mobilisation and ERK1/2 phosphorylation) of each of the naturally occurring endogenous peptide agonists, as well as the clinically used peptide mimetic, exendin-4. We identified and quantified stimulus bias across multiple endogenous peptides, with response profiles for truncated GLP-1 peptides distinct from those of either the full-length GLP-1 peptides or oxyntomodulin; the first demonstration of such behaviour at the GLP-1 receptor. Compound 2 selectively augmented cAMP signalling but did so in a peptide-agonist dependent manner having greatest effect on oxyntomodulin, weaker effect on truncated GLP-1 peptides and negligible effect on other peptide responses; these effects were principally driven by parallel changes in peptide agonist affinity. In contrast, quercetin selectively modulated calcium signalling but with effects only on truncated GLP-1 peptides or exendin and not oxyntomodulin or full-length peptides. These data have significant implications for how GLP-1 receptor targeted drugs are screened and developed, while the allosterically driven, agonist-selective, stimulus bias highlights the potential for distinct clinical efficacy depending on the properties of individual drugs.The American Society for Pharmacology and Experimental Therapeutics