The Ligand-specific Internalization Mechanism Of CMKLR1 And Biphasic Modulation Of Orthosteric Agonist Chemerin C9 By Amyloid Beta Peptide

The chemokine-like receptor 1(CMKLR1, ChemR23) is a functional receptor for chemerin and the chemerin-derived nonapeptide(C9 peptide). A recent study showed that CMKLR1 is also a receptor for the amyloid β peptide 1-42(Aβ42). Because these peptides share little sequence homology, their pharmacological properties at CMKLR1 were compared in transfected cell lines expressing CMKLR1. Binding of both Aβ42 and C9 peptide induced CMKLR1 internalization, but only the Aβ42–induced receptor internalization involved clathrin-coated pits. Likewise, Aβ42 but not C9 peptide stimulated β-arrestin2 translocation to plasma membranes. A robust Ca2+ response was observed following C9 peptide stimulation, whreas Aβ42 was ineffective event at micromolar concenrations. Despite its low potency, the presence of Aβ42 altered C9 peptide-induced Ca2+ flux including potentiation at 100 pM, suppression at 10 nM and futher potentiation at 1 μM. The biphasic modulation of CMKLR1-dependent Ca2+ flux was mirrored in C9 peptide-induced ERK phosphorylation, but in opposite directions. Taken together, these findings suggest novel modulatory features of Aβ42 and C9 peptide, possibly involving biased signaling through CMKLR1 and conformational changes in the receptor structure.