A phytosphingosine derivative mYG-II-6 inhibits histamine-mediated TRPV1 activation and MRGPRX2-dependent mast cell degranulation
- Authors
- Adhikari, Nisha; Lee, Wook-Joo; Park, Soojun; Kim, Sanghee; Shim, Won-Sik
- Issue Date
- May-2024
- Publisher
- Elsevier
- Keywords
- Itch; TRPV1; MRGPRX2; Histamine; Mast cell degranulation
- Citation
- International Immunopharmacology, v.133
- Journal Title
- International Immunopharmacology
- Volume
- 133
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/91454
- DOI
- 10.1016/j.intimp.2024.112113
- ISSN
- 1567-5769
1878-1705
- Abstract
- Background: Phytosphingosine and its derivative are known for their skin-protective properties. While mYG-II-6, a phytosphingosine derivative, has shown anti-inflammatory and antipsoriatic effects, its potential antipruritic qualities have yet to be explored. This study aimed to investigate mYG-II-6 ' s antipruritic properties. Methods: The calcium imaging technique was employed to investigate the activity of ion channels and receptors. Mast cell degranulation was confirmed through the beta-hexosaminidase assay. Additionally, in silico molecular docking and an in vivo mouse scratching behavior test were utilized. Results: Using HEK293T cells transfected with H1R and TRPV1, we examined the impact of mYG-II-6 on histamine-induced intracellular calcium rise, a key signal in itch-mediating sensory neurons. Pretreatment with mYG-II-6 significantly reduced histamine-induced calcium levels and inhibited TRPV1 activity, suggesting its role in blocking the calcium influx channel. Additionally, mYG-II-6 suppressed histamine-induced calcium increase in primary cultures of mouse dorsal root ganglia, indicating its potential antipruritic effect mediated by histamine. Interestingly, mYG-II-6 exhibited inhibitory effects on human MRGPRX2, a G protein-coupled receptor involved in IgE-independent mast cell degranulation. However, it did not inhibit mouse MrgprB2, the ortholog of human MRGPRX2. Molecular docking analysis revealed that mYG-II-6 selectively interacts with the binding pocket of MRGPRX2. Importantly, mYG-II-6 suppressed histamine-induced scratching behaviors in mice. Conclusions: Our findings show that mYG-II-6 can alleviate histamine-induced itch sensation through dual mechanisms. This underscores its potential as a versatile treatment for various pruritic conditions.
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