Icatibant Acts as a Balanced Ligand of MRGPRX2 in Human Skin Mast Cells

MRGPRX2 (Mas-related G protein-coupled receptor member X2) is implicated in mast cell (MC)-driven disorders due to its ability to bind diverse ligands, which may be G-protein-biased or balanced, with the latter activating both G-proteins and the β-arrestin pathway. Icatibant, a peptide drug, produce...

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Published in:Biomolecules (Basel, Switzerland) Vol. 15; no. 9; p. 1224
Main Authors: Li, Zhuoran, Schneikert, Jean, Bal, Gürkan, Zuberbier, Torsten, Babina, Magda
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 25.08.2025
Subjects:
1-Phosphatidylinositol 3-kinase
Agonists
AKT protein
Allergic diseases
Allergic reaction
Allergy
Amino acids
Antibodies
Arrestin
Bradykinin - analogs & derivatives
Bradykinin - metabolism
Bradykinin - pharmacology
c-Jun protein
Calcium channels
Cell Degranulation - drug effects
Cloning
Degranulation
desensitization
drug allergy
Edema
Exocytosis
Experiments
Flow cytometry
G proteins
Humans
Icatibant
Immunoblotting
Internalization
JNK protein
Kinases
Ligands
Mast cells
Mast Cells - drug effects
Mast Cells - metabolism
Membrane proteins
MRGPRX2
Nerve Tissue Proteins - metabolism
Neuropeptides
Proteins
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - metabolism
Receptors, Neuropeptide - metabolism
Signal Transduction - drug effects
Skin
Skin - cytology
Skin - drug effects
Skin - metabolism
Skin tests
Substance P
Substance P - pharmacology
Transcription factors
California
United States
Massachusetts
Germany
St Louis Missouri
United States > US
Berlin Germany
Ireland
LAD2 cell line
signaling
drug allergy
MRGPRX2
degranulation
icatibant
mast cells
desensitization
ISSN:2218-273X, 2218-273X
Online Access:Get full text
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Summary:MRGPRX2 (Mas-related G protein-coupled receptor member X2) is implicated in mast cell (MC)-driven disorders due to its ability to bind diverse ligands, which may be G-protein-biased or balanced, with the latter activating both G-proteins and the β-arrestin pathway. Icatibant, a peptide drug, produces injection-site reactions in most patients and is used experimentally to probe MRGPRX2 function in skin tests. While reported to be G-protein-biased, it is unknown how skin MCs respond to icatibant, although these are the primary target cells during therapy. We therefore compared responses to icatibant with those induced by the balanced agonist substance P (SP) in skin MCs. Degranulation and desensitization were assessed via β-hexosaminidase release, receptor internalization by flow cytometry, and downstream signaling by immunoblotting. Skin MCs degranulated in response to SP and icatibant, relying on Gi proteins and calcium channels; Gq and PI3K (Phosphoinositide 3-kinase) contributed more strongly to exocytosis following icatibant, while JNK (c-Jun n-terminal kinase) was more relevant for SP. Both agonists activated ERK, PI3K/AKT, and (weakly) p38. Surprisingly, and in contrast to the LAD2 (Laboratory of Allergic Diseases 2 mast cell line) MC line, icatibant was at least as potent as SP in eliciting MRGPRX2 internalization and (cross-)desensitization in skin MCs. These findings suggest that icatibant functions differently in primary versus transformed MCs, acting as a fully balanced ligand in the former by triggering not only degranulation but also receptor internalization and desensitization. Therefore, not only the ligand but also the MRGPRX2-expressing cell plays a decisive role in whether a ligand is balanced or biased. These findings are relevant to our understanding of icatibant’s clinical effects on edema and itch.
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ISSN:2218-273X
2218-273X
DOI:10.3390/biom15091224