Understanding allosteric modulation and biased signalling at the glucagon-like peptide-1 receptor
The glucagon-like peptide-1 receptor (GLP1R) is a Class B G protein-coupled receptor (GPCR) that, upon activation, elicits a broad range of complementary effects which are of potential therapeutic benefit in type 2 diabetes. Two major recent developments in GPCR research are (i) activation by different ligands can give rise to distinct signalling profiles (biased signalling) and (ii) some ligands can bind to distinct sites on the receptor to that of the endogenous ligand and either directly activate the receptor and/or modulates the signalling profile of the endogenous ligand (allosteric modulation). These phenomenon hold great promise for successful drug development by sculpting physiological responses, however a critical knowledge gap is a detailed understanding of the signalling pathways that lead to beneficial effects over detrimental effects and the relative importance of different signalling intermediates in exerting these effects.
We offer a range of projects studying the molecular basis and the physiological consequences of biased signalling and allosteric modulation at the GLP1R. These include receptor mutagenesis, molecular modelling and profiling of ligands (including SAR elaborations) across a wide range of cellular endpoints (signalling, (ie cAMP, calcium, ERK phosphorylation etc), receptor trafficking and regulation, cell proliferation and apoptosis, gene regulation, etc) in both recombinant and native cellular expression systems. Translation of key mechanistic findings also requires understanding of these paradigms in model systems of physiology and disease.
We also offer projects examining wild-type and transgenic mice to understand the impact GLP1R-mediated signal bias and allosteric modulation on insulin secretion, glucose homeostasis, islet integrity, gastric emptying and neuronal activation. Model mouse systems include GLP1R knockouts, knock-ins of modified GLP1Rs that selectively activate distinct signalling pathways.