Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/ijms22105318
Keywords
mast cells; MRGPRX2; MrgprB2; tyrosine; substance P; signaling; internalization
Funding
- National Institutes of Health [R01-AI124182, R01-AI143185, R01-AI149487]
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The neuropeptide substance P activates mast cells through MrgprB2, contributing to neurogenic inflammation and pain in atopic dermatitis. Certain MRGPRX2 agonists lead to beta-arrestin recruitment, revealing a new pathway for receptor internalization and desensitization. The study highlights a tyrosine residue in the highly conserved NPxxY motif of MRGPRX2 that plays a role in both G protein- and beta-arrestin-mediated responses.
The neuropeptide substance P (SP) mediates neurogenic inflammation and pain and contributes to atopic dermatitis in mice through the activation of mast cells (MCs) via Mas-related G protein-coupled receptor (GPCR)-B2 (MrgprB2, human ortholog MRGPRX2). In addition to G proteins, certain MRGPRX2 agonists activate an additional signaling pathway that involves the recruitment of beta-arrestins, which contributes to receptor internalization and desensitization (balanced agonists). We found that SP caused beta-arrestin recruitment, MRGPRX2 internalization, and desensitization. These responses were independent of G proteins, indicating that SP serves as a balanced agonist for MRGPRX2. A tyrosine residue in the highly conserved NPxxY motif contributes to the activation and internalization of many GPCRs. We have previously shown that Tyr(279) of MRGPRX2 is essential for G protein-mediated signaling and degranulation. To assess its role in beta-arrestin-mediated MRGPRX2 regulation, we replaced Tyr(279) in the NPxxY motif of MRGPRX2 with Ala (Y279A). Surprisingly, we found that, unlike the wild-type receptor, Y279A mutant of MRGPRX2 was resistant to SP-induced beta-arrestin recruitment and internalization. This study reveals the novel findings that activation of MRGPRX2 by SP is regulated by beta-arrestins and that a highly conserved tyrosine residue within MRGPRX2's NPxxY motif contributes to both G protein- and beta-arrestin-mediated responses.
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