Itch receptor MRGPRX4 interacts with the receptor activity-modifying proteins.

Autor:	Kotliar IB; Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York, USA; Tri-Institutional PhD Program in Chemical Biology, New York, New York, USA., Ceraudo E; Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York, USA., Kemelmakher-Liben K; Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York, USA., Oren DA; Structural Biology Resource Center, The Rockefeller University, New York, New York, USA., Lorenzen E; Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York, USA., Dodig-Crnković T; Science for Life Laboratory, Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden., Horioka-Duplix M; Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York, USA., Huber T; Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York, USA., Schwenk JM; Science for Life Laboratory, Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden., Sakmar TP; Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York, USA; Department of Neurobiology, Care Sciences and Society, Section for Neurogeriatrics, Karolinska Institutet, Solna, Sweden. Electronic address: Sakmar@rockefeller.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 May; Vol. 299 (5), pp. 104664. Date of Electronic Publication: 2023 Mar 30.
DOI:	10.1016/j.jbc.2023.104664
Abstrakt:	Cholestatic itch is a severe and debilitating symptom in liver diseases with limited treatment options. The class A G protein-coupled receptor (GPCR) Mas-related GPCR subtype X4 (MRGPRX4) has been identified as a receptor for bile acids, which are potential cholestatic pruritogens. An increasing number of GPCRs have been shown to interact with receptor activity-modifying proteins (RAMPs), which can modulate different aspects of GPCR biology. Using a combination of multiplexed immunoassay and proximity ligation assay, we show that MRGPRX4 interacts with RAMPs. The interaction of MRGPRX4 with RAMP2, but not RAMP1 or 3, causes attenuation of basal and agonist-dependent signaling, which correlates with a decrease of MRGPRX4 cell surface expression as measured using a quantitative NanoBRET pulse-chase assay. Finally, we use AlphaFold Multimer to predict the structure of the MRGPRX4-RAMP2 complex. The discovery that RAMP2 regulates MRGPRX4 may have direct implications for future drug development for cholestatic itch. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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