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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Vydané v:	Biomolecules (Basel, Switzerland) Ročník 15; číslo 9; s. 1224
Hlavní autori:	Li, Zhuoran, Schneikert, Jean, Bal, Gürkan, Zuberbier, Torsten, Babina, Magda
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Switzerland MDPI AG 25.08.2025
Predmet:	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
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Abstract	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.
AbstractList	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. 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.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.
Audience	Academic
Author	Zuberbier, Torsten Li, Zhuoran Bal, Gürkan Schneikert, Jean Babina, Magda
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Snippet	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...
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SubjectTerms	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
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Title	Icatibant Acts as a Balanced Ligand of MRGPRX2 in Human Skin Mast Cells
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