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

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...

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Bibliographic Details
Published in:Communications biology 2021-06, Vol.4 (1), p.776-776, Article 776
Main Authors: Clark, Ashley J., Mullooly, Niamh, Safitri, Dewi, Harris, Matthew, de Vries, Tessa, MaassenVanDenBrink, Antoinette, Poyner, David R., Gianni, Davide, Wigglesworth, Mark, Ladds, Graham
Format: Article
Language:English
Subjects:
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Adrenomedullin
Agonists
Bias
Biology
Biomedical and Life Sciences
Calcitonin gene-related peptide
Calcium oxide
Calcium signalling
Endothelial cells
G protein-coupled receptors
Life Sciences
Ligands
Nitric oxide
Physiology
Signal transduction
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Summary: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. Clark et al. explore the ability of ligands to activate the calcitonin-like receptor (CLR) in primary endothelial cells, and the influence of co-expressed receptor-activity modifying proteins (RAMPs). Their study reveals that GPCR agonist bias occurs naturally in human cells and plays a fundamental role in providing unique functions to endogenous agonists.
ISSN:2399-3642
2399-3642
DOI:10.1038/s42003-021-02293-w