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.

Lijun Shao;Yan Chen;Shikai Zhang;Zhihui Zhang;Yongbing Cao;Dehua Yang;Ming-Wei Wang

The National Center for Drug Screening and CAS Key Laboratory of Receptor Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences(CAS),Shanghai 201203,China;School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,China;University of Chinese Academy of Sciences,Beijing 100049,China;School of Pharmacy,Fudan University,Shanghai 201203,China;Shanghai TCM-Integrated Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai 200082,China;Department of Pharmacology,School of Basic Medical Sciences,Fudan University,Shanghai 200032,China

药学学报（英文版）

[1]Lijun Shao;Yan Chen;Shikai Zhang;Zhihui Zhang;Yongbing Cao;Dehua Yang;Ming-Wei Wang-.Modulating effects of RAMPs on signaling profiles of the glucagon receptor family)[J].药学学报（英文版）,2022(02):637-650

RAMPs,arrestin1,RAMPl,RAMP2

Modulating,effects,signaling,profiles,glucagon,family,Receptor,activity,modulating,proteins,are,accessory,molecules,that,form,plexes,specific,coupled,receptors,GPCRs,their,functions,It,established,interacts,but,underlying,mechanism,poorly,understood,In,this,study,used,bioluminescence,resonance,energy,transfer,BRET,approach,comprehensively,investigate,such,interactions,conjunction,cAMP,accumulation,recruitment,assays,not,only,verified,pairs,previously,ported,also,identified,new,patterns,While,was,able,modify,three,events,elicited,by,both,GCGR,like,GLP,1R,mainly,affected,peptide,RAMP3,showed,widespread,negative,impact,all,members,except,growth,hormone,releasing,covering,pathways,Our,sults,suggest,modulates,independent,transduction,among,manner,Mapping,provides,insights,into,role,ligand,recognition,activation

0.543056