Ligand-directed Bias and Polymorphic Variation in the Glucagon-like Peptide-1 Receptor: Implications for Drug Discovery

Program: G Protein-Coupled Receptors Forum
Session: GPCR-Symposium 1: Consequences of Structural Variation in GPCRs and their Ligands on Receptor Function
Tuesday, June 18, 2013: 1:35 PM-3:35 PM
Presentation Start Time: 2:15 PM
Nob Hill (San Francisco Marriott Marquis)
Patrick Sexton*
Monash University, Parkville Vic, Australia
Talk Description:

The glucagon-like peptide-1 receptor (GLP1R) is a Family B G protein-coupled receptor (GPCR) that plays an essential role in nutrient regulated insulin release, and has emerged as a major target for therapeutic treatment of type 2 diabete. In recent years, a number of important paradigms have arisen that challenge traditional views of signalling and regulation at GPCRs. These include the recognition of non-canonical (G protein-independent) signalling (in particular that mediated by regulatory proteins like β-arrestins (βArrs)) and the ability of individual ligands to couple to distinct functional outcomes with differing prominence (termed ligand-induced signal bias). These paradigms may provide novel opportunities to develop pathway-selective therapeutics, but could also contribute to adverse side effect profiles. In addition, the GLP1R has multiple polymorphic variants, one of which results in marked loss of response to peptide agonists. Allosteric ligands offer a potential mechanism for functional rescue for these variants. This talk will explore our current knowledge of ligand-directed signal bias at the GLP1R and the effect of polymorphic variation on receptor signaling.