posted on 2021-03-22, 05:05authored byMax Meyrath, Christie B. Palmer, Nathan Reynders, Alain Vanderplasschen, Markus Ollert, Michel Bouvier, Martyna Szpakowska, Andy Chevigné
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).