摘要Receptor activity-modulating proteins(RAMPs)are accessory molecules that form com-plexes with specific G protein-coupled receptors(GPCRs)and modulate their functions.It is established that RAMP interacts with the glucagon receptor family of GPCRs but the underlying mechanism is poorly understood.In this study,we used a bioluminescence resonance energy transfer(BRET)approach to comprehensively investigate such interactions.In conjunction with cAMP accumulation,Gαq activa-tion and β-arrestin1/2 recruitment assays,we not only verified the GPCR-RAMP pairs previously re-ported,but also identified new patterns of GPCR-RAMP interaction.While RAMPl was able to modify the three signaling events elicited by both glucagon receptor(GCGR)and glucagon-like pep-tide-1 receptor(GLP-1R),and RAMP2 mainly affected β-arrestin 1/2 recruitment by GCGR,GLP-1R and glucagon-like peptide-2 receptor,RAMP3 showed a widespread negative impact on all the family members except for growth hormone-releasing hormone receptor covering the three pathways.Our re-sults suggest that RAMP modulates both G protein dependent and independent signal transduction among the glucagon receptor family members in a receptor-specific manner.Mapping such interactions provides new insights into the role of RAMP in ligand recognition and receptor activation.