TY - JOUR
T1 - Proadrenomedullin N-Terminal 20 Peptides (PAMPs) Are Agonists of the Chemokine Scavenger Receptor ACKR3/CXCR7
AU - Meyrath, Max
AU - Palmer, Christie B.
AU - Reynders, Nathan
AU - Vanderplasschen, Alain
AU - Ollert, Markus
AU - Bouvier, Michel
AU - Szpakowska, Martyna
AU - Chevigné, Andy
N1 - Funding Information:
This study was supported by the Luxembourg Institute of Health (LIH), Luxembourg National Research Fund INTER/FWO “Nanokine” grant 15/10358798, INTER/FNRS grants 20/15084569 and PoC “Megakine” 19/14209621, F.R.S.-FNRS-Télévie (grants 7.4593.19, 7.4526.19, and 7.8504.20) and PRIDE-14254520 “I2TRON”. M.M., C.P., and N.R. are Luxembourg National Research Fund Ph.D. fellows (grants AFR-3004509 and AFR-14616593; PRIDE-11012546 “NextImmune”). C.P. is of part of the Marie Skłodowska-Curie Innovative Training Networks ONCORNET2.0 “ONCOgenic Receptor Network of Excellence and Training” (MSCA-ITN-2019). M.B. is supported by a Foundation grant from the Canadian Institute for Health Research (FDN-148431) and holds the Canada Research Chair in Signal Transduction and Molecular Pharmacology. The authors wish to thank Manuel Counson, Nadia Beaupain, and Jean-Marc Plesseria for technical help and support.
Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/4/9
Y1 - 2021/4/9
N2 - Adrenomedullin (ADM) and proadrenomedullin N-terminal 20 peptide (PAMP) are two peptides with vasodilative, bronchodilative, and angiogenic properties, originating from a common precursor, proADM. Previous studies proposed that the atypical chemokine receptor ACKR3 might act as a low-affinity scavenger for ADM, regulating its availability for its cognate receptor calcitonin receptor-like receptor (CLR) in complex with a receptor activity modifying protein (RAMP). In this study, we compared the activation of ACKR3 by ADM and PAMP, as well as other related members of the calcitonin gene-related peptide (CGRP) family. Irrespective of the presence of RAMPs, ADM was the only member of the CGRP family to show moderate activity toward ACKR3. Remarkably, PAMP, and especially further processed PAMP-12, had a stronger potency toward ACKR3 than ADM. Importantly, PAMP-12 induced β-arrestin recruitment and was efficiently internalized by ACKR3 without inducing G protein or ERK signaling in vitro. Our results further extend the panel of endogenous ACKR3 ligands and broaden ACKR3 functions to a regulator of PAMP-12 availability for its primary receptor Mas-related G-protein-coupled receptor member X2 (MrgX2).
AB - Adrenomedullin (ADM) and proadrenomedullin N-terminal 20 peptide (PAMP) are two peptides with vasodilative, bronchodilative, and angiogenic properties, originating from a common precursor, proADM. Previous studies proposed that the atypical chemokine receptor ACKR3 might act as a low-affinity scavenger for ADM, regulating its availability for its cognate receptor calcitonin receptor-like receptor (CLR) in complex with a receptor activity modifying protein (RAMP). In this study, we compared the activation of ACKR3 by ADM and PAMP, as well as other related members of the calcitonin gene-related peptide (CGRP) family. Irrespective of the presence of RAMPs, ADM was the only member of the CGRP family to show moderate activity toward ACKR3. Remarkably, PAMP, and especially further processed PAMP-12, had a stronger potency toward ACKR3 than ADM. Importantly, PAMP-12 induced β-arrestin recruitment and was efficiently internalized by ACKR3 without inducing G protein or ERK signaling in vitro. Our results further extend the panel of endogenous ACKR3 ligands and broaden ACKR3 functions to a regulator of PAMP-12 availability for its primary receptor Mas-related G-protein-coupled receptor member X2 (MrgX2).
KW - ACKR3
KW - CXCR7
KW - MRGPRX2
KW - PAMP-12
KW - RAMP
KW - adrenomedullin
UR - http://www.scopus.com/inward/record.url?scp=85104925938&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/33860204
U2 - 10.1021/acsptsci.1c00006
DO - 10.1021/acsptsci.1c00006
M3 - Article
C2 - 33860204
AN - SCOPUS:85104925938
SN - 2575-9108
VL - 4
SP - 813
EP - 823
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
IS - 2
ER -