CGRP, adrenomedullin and adrenomedullin 2 display endogenous GPCR agonist bias in primary human cardiovascular cells

Clark A.J., Mullooly N., Safitri D., Harris M., de Vries T., MaassenVanDenBrink A., Poyner D.R., Gianni D., Wigglesworth M., Ladds G.

Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom; Functional Genomics, Discovery Sciences, R&D, AstraZeneca, Cambridge, United Kingdom; Pharmacology and Clinical Pharmacy Research Group, School of Pharmacy, Bandung Institute of Technology, Bandung, Indonesia; Department of Internal Medicine, Erasmus MC, Erasmus University Medical Centre, Rotterdam, Rotterdam, Netherlands; School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, United Kingdom; Hit Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Alderley Park, United Kingdom


Abstract

Agonist bias occurs when different ligands produce distinct signalling outputs when acting at the same receptor. However, its physiological relevance is not always clear. Using primary human cells and gene editing techniques, we demonstrate endogenous agonist bias with physiological consequences for the calcitonin receptor-like receptor, CLR. By switching the receptor-activity modifying protein (RAMP) associated with CLR we can “re-route” the physiological pathways activated by endogenous agonists calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2). AM2 promotes calcium-mediated nitric oxide signalling whereas CGRP and AM show pro-proliferative effects in cardiovascular cells, thus providing a rationale for the expression of the three peptides. CLR-based agonist bias occurs naturally in human cells and has a fundamental purpose for its existence. We anticipate this will be a starting point for more studies into RAMP function in native environments and their importance in endogenous GPCR signalling. © 2021, The Author(s).


Journal

Communications Biology

Publisher: Nature Research

Volume 4, Issue 1, Art No 776, Page – , Page Count


Journal Link: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85108831783&doi=10.1038%2fs42003-021-02293-w&partnerID=40&md5=c88e947fb6dd41722b360602173dda8c

doi: 10.1038/s42003-021-02293-w

Issn: 23993642

Type: All Open Access, Gold, Green


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