Determination of key residues in MRGPRX2 to enhance pseudo-allergic reactions induced by fluoroquinolones
Abstract MAS-related G protein-coupled receptor X2 (MRGPRX2), expressed in human mast cells, is associated with drug-induced pseudo-allergic reactions. Dogs are highly sensitive to the anaphylactoid reactions induced by certain drugs including fluoroquinolones. Recently, dog MRGPRX2 was identified a...
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Nature Portfolio
2022-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-10549-6 |
| _version_ | 1818523837023649792 |
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| author | Eri Hamamura-Yasuno Junya Matsushita Seiji Sato Takashi Shimada Yoshimi Tsuchiya Kazunori Fujimoto Kazuhiko Mori |
| author_facet | Eri Hamamura-Yasuno Junya Matsushita Seiji Sato Takashi Shimada Yoshimi Tsuchiya Kazunori Fujimoto Kazuhiko Mori |
| author_sort | Eri Hamamura-Yasuno |
| collection | DOAJ |
| description | Abstract MAS-related G protein-coupled receptor X2 (MRGPRX2), expressed in human mast cells, is associated with drug-induced pseudo-allergic reactions. Dogs are highly sensitive to the anaphylactoid reactions induced by certain drugs including fluoroquinolones. Recently, dog MRGPRX2 was identified as a functional ortholog of human MRGPRX2, with dog MRGPRX2 being particularly sensitive to fluoroquinolones. The aim of this study was to determine key residues responsible for the enhanced activity of fluoroquinolone-induced histamine release associated with MRGPRX2. Firstly, a structure model of human and dog MRGPRX2 was built by homology modeling, and docking simulations with fluoroquinolones were conducted. This model indicated that E164 and D184, conserved between human and dog, are essential for the binding to fluoroquinolones. In contrast, F78 (dog: Y) and M109 (dog: W) are unconserved residues, to which the species difference in fluoroquinolone sensitivity is attributable. Intracellular calcium mobilisation assay with human MRGPRX2 mutants, in which residues at positions 78 and 109 were substituted to those of dog MRGPRX2, revealed that M109 and F78 of human MRGPRX2 are crucial residues for enhancing the fluoroquinolone-induced histamine release. In conclusion, these key residues have important clinical implications for revealing the mechanisms and predicting the risks of fluoroquinolone-mediated pseudo-allergic reactions in humans. |
| first_indexed | 2024-12-11T05:49:38Z |
| format | Article |
| id | doaj.art-58b9c8f72ca1483da5463310a8937256 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-11T05:49:38Z |
| publishDate | 2022-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-58b9c8f72ca1483da5463310a89372562022-12-22T01:18:51ZengNature PortfolioScientific Reports2045-23222022-04-011211910.1038/s41598-022-10549-6Determination of key residues in MRGPRX2 to enhance pseudo-allergic reactions induced by fluoroquinolonesEri Hamamura-Yasuno0Junya Matsushita1Seiji Sato2Takashi Shimada3Yoshimi Tsuchiya4Kazunori Fujimoto5Kazuhiko Mori6Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.Modality Research Laboratories, Daiichi Sankyo Co., Ltd.Organic & Biomolecular Chemistry Department, Daiichi Sankyo RD Novare Co., Ltd.Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.Daiichi Sankyo RD Novare Co., Ltd.Abstract MAS-related G protein-coupled receptor X2 (MRGPRX2), expressed in human mast cells, is associated with drug-induced pseudo-allergic reactions. Dogs are highly sensitive to the anaphylactoid reactions induced by certain drugs including fluoroquinolones. Recently, dog MRGPRX2 was identified as a functional ortholog of human MRGPRX2, with dog MRGPRX2 being particularly sensitive to fluoroquinolones. The aim of this study was to determine key residues responsible for the enhanced activity of fluoroquinolone-induced histamine release associated with MRGPRX2. Firstly, a structure model of human and dog MRGPRX2 was built by homology modeling, and docking simulations with fluoroquinolones were conducted. This model indicated that E164 and D184, conserved between human and dog, are essential for the binding to fluoroquinolones. In contrast, F78 (dog: Y) and M109 (dog: W) are unconserved residues, to which the species difference in fluoroquinolone sensitivity is attributable. Intracellular calcium mobilisation assay with human MRGPRX2 mutants, in which residues at positions 78 and 109 were substituted to those of dog MRGPRX2, revealed that M109 and F78 of human MRGPRX2 are crucial residues for enhancing the fluoroquinolone-induced histamine release. In conclusion, these key residues have important clinical implications for revealing the mechanisms and predicting the risks of fluoroquinolone-mediated pseudo-allergic reactions in humans.https://doi.org/10.1038/s41598-022-10549-6 |
| spellingShingle | Eri Hamamura-Yasuno Junya Matsushita Seiji Sato Takashi Shimada Yoshimi Tsuchiya Kazunori Fujimoto Kazuhiko Mori Determination of key residues in MRGPRX2 to enhance pseudo-allergic reactions induced by fluoroquinolones Scientific Reports |
| title | Determination of key residues in MRGPRX2 to enhance pseudo-allergic reactions induced by fluoroquinolones |
| title_full | Determination of key residues in MRGPRX2 to enhance pseudo-allergic reactions induced by fluoroquinolones |
| title_fullStr | Determination of key residues in MRGPRX2 to enhance pseudo-allergic reactions induced by fluoroquinolones |
| title_full_unstemmed | Determination of key residues in MRGPRX2 to enhance pseudo-allergic reactions induced by fluoroquinolones |
| title_short | Determination of key residues in MRGPRX2 to enhance pseudo-allergic reactions induced by fluoroquinolones |
| title_sort | determination of key residues in mrgprx2 to enhance pseudo allergic reactions induced by fluoroquinolones |
| url | https://doi.org/10.1038/s41598-022-10549-6 |
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