Glucagon-like peptide-1 receptor internalisation controls spatiotemporal signalling mediated by biased agonists.

Glucagon-like peptide-1 receptor internalisation controls spatiotemporal signalling mediated by biased agonists. Biochem Pharmacol. 2018 Sep 06;: Authors: Fletcher MM, Halls ML, Zhao P, Clydesdale L, Christopoulos A, Sexton PM, Wootten D Abstract The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target in the treatment of type 2 diabetes due to its roles in regulating blood glucose and in promoting weight loss. Like many GPCRs, it is pleiotropically coupled, can be activated by multiple ligands and is subject to biased agonism. The GLP-1R undergoes agonist mediated receptor internalisation that may be associated with spatiotemporal control of signalling and biased agonism, although to date, this has not been extensively explored. Here, we investigate GLP-1R trafficking and its importance with regard to signalling, including the localisation of key signalling molecules, mediated by biased peptide agonists that are either endogenous GLP-1R ligands or are used clinically. Each of the agonists promoted receptor internalisation through a dynamin and caveolae dependent mechanism and traffic the receptor to both degradative and recycling pathways. This internalisation is important for signalling, with cAMP and ERK1/2 phoshorylation (pERK1/2) generated by both plasma membrane localised and internalised receptors. Further assessment of pERK1/2 revealed that all peptides induced nuclear ERK activity, but ligands, liraglutide...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research