MRGPRX2 Is the Codeine Receptor of Human Skin Mast Cells: Desensitization through β-Arrestin and Lack of Correlation with the FcεRI Pathway.
Cell Degranulation
/ drug effects
Cells, Cultured
Codeine
/ pharmacology
Humans
Mast Cells
/ drug effects
Nerve Tissue Proteins
/ physiology
Receptors, G-Protein-Coupled
/ physiology
Receptors, IgE
/ physiology
Receptors, Neuropeptide
/ physiology
Receptors, Opioid
/ physiology
Signal Transduction
/ physiology
Skin
/ drug effects
beta-Arrestins
/ physiology
Journal
The Journal of investigative dermatology
ISSN: 1523-1747
Titre abrégé: J Invest Dermatol
Pays: United States
ID NLM: 0426720
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
01
06
2020
revised:
23
08
2020
accepted:
17
09
2020
pubmed:
16
10
2020
medline:
16
11
2021
entrez:
15
10
2020
Statut:
ppublish
Résumé
Codeine stimulates skin mast cells and is therefore used in skin tests and as an inducer of experimental itch. MRGPRX2 responds to various drugs, including opioids, to elicit pseudoallergic reactions, but whether it represents the main opiate receptor of skin mast cells remains unknown. By combining a number of approaches, including the silencing of MRGPRX2, we now report that MRGPRX2 is indeed the dominant codeine receptor of dermal mast cells. Activation by codeine displayed profound subject variability and correlated with secretion elicited by compound 48/80 or substance P but not by FcεRI aggregation. Degranulation by codeine was attenuated by stem cell factor, whereas the opposite was found for FcεRI. Compound 48/80 or codeine alone was able to achieve maximum MRGPRX2 activation. MRGPRX2 was rapidly internalized on codeine binding in a β-arrestin-1‒dependent manner. Codeine-triggered β-arrestin activation was also established by the Tango assay. Prestimulation with MRGPRX2 agonists (but not C3a or FcεRI aggregation) resulted in refractoriness to further stimulation by the same or another MRGPRX2 ligand (cross desensitization). This was duplicated in a cell line (RBL-MRGPRX2). Collectively, codeine degranulates skin mast cells through MRGPRX2, at which it acts as a balanced ligand. It has yet to be determined whether codeine-induced refractoriness could be exploited to desensitize MRGPRX2 to prevent severe pseudoallergic reactions.
Identifiants
pubmed: 33058860
pii: S0022-202X(20)32150-3
doi: 10.1016/j.jid.2020.09.017
pmc: PMC8041898
mid: NIHMS1637007
pii:
doi:
Substances chimiques
MRGPRX2 protein, human
0
Nerve Tissue Proteins
0
Receptors, G-Protein-Coupled
0
Receptors, IgE
0
Receptors, Neuropeptide
0
Receptors, Opioid
0
beta-Arrestins
0
Codeine
UX6OWY2V7J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1286-1296.e4Subventions
Organisme : NIAID NIH HHS
ID : R01 AI124182
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI149487
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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