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Updated: Oct 13, 2025
04:59
Cheek Injection Model for Simultaneous Measurement of Pain and Itch-related Behaviors
Published on: September 27, 2019
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Structure, function and pharmacology of human itch GPCRs
Can Cao1, Hye Jin Kang1, Isha Singh2
1Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Nature
|November 18, 2021
Summary
Researchers uncovered the structures of itch-related receptors MRGPRX2 and MRGPRX4. This breakthrough advances the development of new treatments for pain, itch, and hypersensitivity reactions.
Area of Science:
- Pharmacology
- Structural Biology
- Immunology
Background:
- The Mas-related G-protein-coupled receptor (MRGPRX) family, including MRGPRX1-4, has recently evolved.
- MRGPRX2 and MRGPRX4 are critical mediators of itch and mast cell-mediated hypersensitivity.
- MRGPRX2 signals through both Gi and Gq pathways in mast cells.
Purpose of the Study:
- To determine the agonist-stabilized structures of MRGPRX2 and MRGPRX4.
- To develop potent antagonist probes for MRGPRX2.
- To facilitate structure-guided drug discovery for itch and hypersensitivity.
Main Methods:
- Determined ternary complex structures of MRGPRX2 with Gi1 and Gq using cortistatin-14 and a synthetic agonist.
- Developed potent antagonist probes targeting MRGPRX2.
- Characterized a specific MRGPRX4 agonist and its complex structure with Gq.
Main Results:
- Provided agonist-stabilized structures for MRGPRX2 in complex with Gi1 and Gq.
- Identified a specific agonist for MRGPRX4 and its structural complex with Gq.
- Developed novel MRGPRX2 antagonist probes.
Conclusions:
- Structural insights into MRGPRX2 and MRGPRX4 activation mechanisms.
- The findings pave the way for targeted therapeutic development.
- Accelerates the discovery of agents for treating pain, itch, and hypersensitivity.
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