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

Ashley Clark, Niamh Mullooly, Dewi Safitri, Matthew Harris, Tessa de Vries, Antoinette Maassen Van Den Brink, David Poyner, Davide Gianni, Mark Wrigglesworth, Graham Ladds*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 for the first time, 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
Original languageEnglish
Article number776
JournalCommunications Biology
Publication statusPublished - 23 Jun 2021

Bibliographical note

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Funding: This work was supported by the Biotechnology and Biological Sciences Research Council [grant number BB/M000176/2] awarded to GL and DRP, a Medical Research Council Confidence in Concept award to GL and MH (MC_PC_17156) and the Endowment Fund for education from Ministry of Finance Republic of Indonesia (DS). AJC is funded through an AstraZeneca Scholarship.


  • Calcitonin
  • Receptor pharmacology


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