title: Modulation of the glucagon-like peptide-1 receptor signaling by naturally occurring and synthetic flavonoids.
abstract: The glucagon-like peptide 1 receptor (GLP-1R) is a promising target for the treatment of type II diabetes mellitus because of its role in metabolic homeostasis. In recent years, difficulties with peptide therapies have driven the search for small-molecule compounds to modulate the activity of this receptor. We recently identified quercetin, a naturally occurring flavonoid, as a probe-dependent, pathway-selective allosteric modulator of GLP-1R-mediated signaling. Using Chinese hamster ovary cells expressing the human GLP-1R, we have now extended this work to identify the structural requirements of flavonoids to modify GLP-1R binding and signaling (cAMP formation and intracellular Ca(2+) mobilization) of each of the GLP-1R endogenous agonists, as well as the clinically used exogenous peptide mimetic exendin-4. This study identified a chemical series of hydroxyl flavonols with the ability to selectively augment calcium (Ca(2+)) signaling in a peptide agonist-specific manner, with effects only on truncated GLP-1 peptides [GLP-1(7-36)NH(2) and GLP-1(7-37)] and exendin-4, but not on oxyntomodulin or full-length GLP-1 peptides [GLP-1(1-36)NH(2) and GLP-1(1-37)]. In addition, the 3-hydroxyl group on the flavone backbone (i.e., a flavonol) was essential for this activity, however insufficient on its own, to produce the allosteric effects. In contrast to hydroxyl flavonols, catechin had no effect on peptide-mediated Ca(2+) signaling but negatively modulated peptide-mediated cAMP formation in a probe-dependent manner. These data represent a detailed examination of the action of different flavonoids on peptide agonists at the GLP-1R and may aid in the development of future small molecule compounds targeted at this receptor.
authors.affiliation: Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia.
authors.forename: Denise
authors.initials: D
authors.lastname: Wootten
authors.forename: John
authors.initials: J
authors.lastname: Simms
authors.forename: Cassandra
authors.initials: C
authors.lastname: Koole
authors.forename: Owen L
authors.initials: OL
authors.lastname: Woodman
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Summers
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
mesh_terms: D016475:3T3 Cells; D000818:Animals; D016466:CHO Cells; D020013:Calcium Signaling / Q000187:drug effects; D002392:Catechin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D005419:Flavonoids / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D051379:Mice; D018027:Receptors, Glucagon / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D005419:Flavonoids; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; D002392:Catechin