MRGPRX4 mediates phospho-drug–associated pruritus in a humanized mouse model

Author:

Chien Daphne Chun-Che1ORCID,Limjunyawong Nathachit1ORCID,Cao Can2ORCID,Meixiong James3ORCID,Peng Qi1,Ho Cheng-Ying4ORCID,Fay Jonathan F.5ORCID,Roth Bryan L.2ORCID,Dong Xinzhong1678ORCID

Affiliation:

1. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

2. Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.

3. Department of Dermatology, University of California San Francisco, San Francisco, CA 94115, USA.

4. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

5. Department of Biochemistry and Molecular Biology, University of Maryland Baltimore, Baltimore, MD 21201, USA.

6. Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

7. Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

8. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

Abstract

The phosphate modification of drugs is a common chemical strategy to increase solubility and allow for parenteral administration. Unfortunately, phosphate modifications often elicit treatment- or dose-limiting pruritus through an unknown mechanism. Using unbiased high-throughput drug screens, we identified the Mas-related G protein–coupled receptor X4 (MRGPRX4), a primate-specific, sensory neuron receptor previously implicated in itch, as a potential target for phosphate-modified compounds. Using both G q -mediated calcium mobilization and G protein–independent GPCR assays, we found that phosphate-modified compounds potently activate MRGPRX4. Furthermore, a humanized mouse model expressing MRGPRX4 in sensory neurons exhibited robust phosphomonoester prodrug–evoked itch. To characterize and confirm this interaction, we further determined the structure of MRGPRX4 in complex with a phosphate-modified drug through single-particle cryo–electron microscopy (cryo-EM) and identified critical amino acid residues responsible for the binding of the phosphate group. Together, these findings explain how phosphorylated drugs can elicit treatment-limiting itch and identify MRGPRX4 as a potential therapeutic target to suppress itch and to guide future drug design.

Publisher

American Association for the Advancement of Science (AAAS)

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Advances in GPCR-targeted drug development in dermatology;Trends in Pharmacological Sciences;2024-08

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3