Receptor activity-modifying protein 3 enhances GLP-1-mediated insulin secretion

The targeting of the glucagon-like peptide-1 (GLP-1) receptor for diabetes and obesity is not a novel strategy, with recent therapeutics showing efficacy in weight loss and glycemic control. However, they are also associated with side effects, including gastrointestinal disruptions and pancreatitis. Developing agonists with different signaling 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 signaling, as well as surface expression. The GLP-1 receptor was found to interact with RAMP3, with the heterodimer able to bind agonists at the cell surface. RAMP3 expression biased the receptor toward Ca²⁺ mobilization, away from the canonical cAMP-driven signaling. When examining G protein coupling, the interaction with RAMP3 reduced activation of the cognate Gα_s but increased secondary couplings to Gα_q and Gα_i. These increased couplings led to an elevation in glucose-stimulated insulin secretion when cells overexpressing RAMP3 were stimulated with GLP-1. A reciprocal effect was observed when looking at reduced expression of endogenous RAMP3, with a loss of sensitivity to GLP-1 in both glucose and insulin tolerance tests in a Ramp3 KO mouse model. The effects of this interaction can then inform the selection of models and peptide design when targeting this receptor for therapeutic intervention.