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


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Authors
Clark, Ashley J. 
Mullooly, Niamh 
Safitri, Dewi 
Harris, Matthew 
de Vries, Tessa 
Abstract

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.

Description
Keywords
Article, /631/92/436/2387, /631/45/776/814, /96/95, /38/23, /13/95, /13/106, /45/41, article
Journal Title
Communications Biology
Conference Name
Journal ISSN
2399-3642
Volume Title
4
Publisher
Nature Publishing Group UK
Sponsorship
RCUK | Biotechnology and Biological Sciences Research Council (BBSRC) (BB/M000176/2)
RCUK | Medical Research Council (MRC) (MC_PC_17156)