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

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 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

Publication DOI: https://doi.org/10.1038/s42003-021-02293-w
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. 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.
Uncontrolled Keywords: Calcitonin,Receptor pharmacology,Medicine (miscellaneous),Biochemistry, Genetics and Molecular Biology(all),Agricultural and Biological Sciences(all)
Full Text Link:
Related URLs: https://www.nat ... 003-021-02293-w (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2021-06-23
Accepted Date: 2021-06-03
Authors: Clark, Ashley
Mullooly, Niamh
Safitri, Dewi
Harris, Matthew
de Vries, Tessa
Maassen Van Den Brink, Antoinette
Poyner, David (ORCID Profile 0000-0003-1590-112X)
Gianni, Davide
Wrigglesworth, Mark
Ladds, Graham

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