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192P London, UK Pharmacology 2017 |
Modulation of chemerin peptide-induced calcium flux and ERK phosphorylation by amyloid beta peptide
Introduction: The chemokine-like receptor 1 (CMKLR1, ChemR23)[1] is a functional receptor for chemerin, the chemerin-derived nonapeptide (C9), and the amyloid β peptide 1-42 (Aβ42)[2-4]. Because these peptides share little sequence homology, studies were conducted to investigate their pharmacological properties and regulation at CMKLR1.
Methods: Cells expressing CMKLR1 were incubated with Aβ42 before stimulation with another agonist, the C9 peptide. Calcium mobilization, cAMP inhibition and MAP kinase activation were measured. Intramolecular FRET were determined using CMKLR1 constructs containing an ECFP attached to the C- terminus.
Results: Binding of both Aβ42 and the C9 peptide induced CMKLR1 internalization, but only the Aβ42-induced receptor internalization involved clathrin-coated pits. Likewise, Aβ42 but not C9 stimulated β-arrestin2 translocation to plasma membranes. A robust Ca2+ flux was observed following C9 stimulation, whereas Aβ42 was ineffective even at micromolar concentrations. Despite its low potency in calcium mobilization assay, Aβ42 was able to alter C9 -induced Ca2+ flux with potentiation as low as 0.1 - 1 nM of Aβ42. However, at higher concentrations the effect was diminished. A similar effect was also seen with the C9-induced ERK phosphorylation but the dose curve was different from that of Ca2+ flux and cAMP inhibition, suggesting a reciprocal regulatory mechanism. Intramolecular FRET assay confirmed that Aβ42 modulates CMKLR1 rather than its downstream signaling pathways.
Conclusion: These findings suggest Aβ42 can differentially modulate the activation state of CMKLR1 triggered by the C9 peptide of chemerin and its downstream signaling, in a manner that differs from the known modulatory mechanisms [5].
References:
1. Gantz I et al.(1996). Cytogenet Cell Genet 74:286-290.
2. Wittamer V et al. (2003). J Exp Med 198:977-985.
3. Wittamer V et al. (2004). J Biol Chem 279:9956-9962.
4. Peng L et al. (2015). J Alzheimers Dis 43:227-242.
5. De Henau O et al. (2016). PLoS One 11:e0164179-0164179.