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PreprintCited by 20Receptor Mechanisms and SignalingIon Channels and ReceptorsNeuropeptides and Animal Physiology

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Itch receptor MRGPRX4 interacts with the receptor activity-modifying proteins (RAMPs)

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Kotliar, Ilana B., Ceraudo, Emilie, Kemelmakher-Liben, Kevin, Oren, Deena A., Lorenzen, Emily, Dodig-Crnković, Tea, Horioka-Duplix, Mizuho, Huber, Thomas, Schwenk, Jochen M., Sakmar, Thomas P.·2022·Journal of Biological Chemistry
DOI 10.1101/2022.12.06.519316PMC PMC10165273

Preprint — published as 10.1016/j.jbc.2023.104664 · Paper page

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Abstract

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.

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Metadata

Authors
Kotliar, I. B., Ceraudo, E., Kemelmakher-Liben, K., Oren, D. A., Lorenzen, E., Dodig-Crnković, T., Horioka-Duplix, M., Huber, T., Schwenk, J. M., & Sakmar, T. P.
Affiliations
  • Tri-Institutional PhD Program in Chemical Biology (US)
  • Rockefeller University (US)
  • Science for Life Laboratory (SE)
  • Karolinska Institutet (SE)
Corresponding author
Sakmar, Thomas P.
ORCID
Venue
Journal of Biological Chemistry
Publisher
openRxiv
Published
2022-12-06
Volume
299
Issue
5
Pages
104664-104664
ISSN
0021-9258 (ISSN-L)
DOI
10.1101/2022.12.06.519316
PMC
PMC10165273
OpenAlex
W4361264976
Cited by
20
References
1
Citations by year
2026: 11 · 2025: 2 · 2024: 7
FWCI
1.77
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Familjen Erling-Perssons Stiftelse
  • Rockefeller University (SCR_017732)
  • Robertson Foundation
  • Health Promotion Agency
  • Knut och Alice Wallenbergs Stiftelse
  • National Institutes of Health
  • National Institute of General Medical Sciences (T32GM136640)
  • Precursory Research for Embryonic Science and Technology
  • Brain Injury Research Center
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
receptor activity-modifying proteins, RAMP2, pruritus, bile acids, G protein-coupled receptor signaling, receptor complex structure, cell surface expression, liver disease
MeSH terms
Cell Membrane, Humans, Protein Binding, Pruritus, Signal Transduction, Receptors, G-Protein-Coupled, Receptor Activity-Modifying Proteins, Receptor Activity-Modifying Protein 1, Receptor Activity-Modifying Protein 2, Receptor Activity-Modifying Protein 3

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