Increased RAMP3 expression enhances GLP-1 mediated Glucose Stimulated Insulin Secretion in a Manner Dependent on Ca2+ Mobilisation
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
The targeting of the Glucagon-like peptide-1 receptor (GLP-1R) for diabetes and obesity is not a novel strategy, with recent therapeutics showing efficacy in weight loss and glycaemic control. However, they are also associated with side effects, including gastrointestinal disruptions and pancreatitis. Developing agonists with different signalling profiles, or that exert some tissue selectivity can circumvent these on-target, unwanted effects. Receptor activity-modifying proteins (RAMPs) offer the potential to do both, through modulation of agonist binding and signalling, as well as surface expression. The GLP-1R was found to interact with RAMP3, with the heterodimer able to bind agonist at the cell surface. RAMP3 expression biased the receptor towards Ca2+ mobilisation, away from the canonical cAMP-driven signalling. When examining G protein coupling, the interaction with RAMP3 reduced activation of the cognate Gαs, but increased secondary couplings to Gαq and Gαi. These increased couplings led to an elevation in glucose-stimulated insulin secretion when cells overexpressing RAMP3 were stimulated with GLP-1. The effects of this interaction can then inform selection of models and peptide design when targeting this receptor for therapeutic intervention.
Significance Statement
G Protein-Coupled Receptors, such as the Glucagon-Like Peptide-1 (GLP-1) Receptor are common drug targets, although not without side effects due to on-target, unwanted signalling outputs. This study identifies an interacting protein, which alters its signalling to promote insulin secretion. This may improve the therapeutic potential of GLP-1 mimetics, by enhancing effectual signalling over that associated with unwanted effects, by directly targeting this receptor complex.
