1. Methiothepin downregulates SNAP-23 and inhibits degranulation of rat basophilic leukemia cells and mouse bone marrow-derived mast cells.
- Author
-
Kondo D, Suzuki R, Matsumura A, Meguri H, Tanaka M, Itakura M, and Hirashima N
- Subjects
- Rats, Mice, Animals, Methiothepin metabolism, Methiothepin pharmacology, I-kappa B Kinase metabolism, Serotonin pharmacology, Serotonin metabolism, Bone Marrow metabolism, Ionomycin metabolism, Ionomycin pharmacology, Serotonin Antagonists metabolism, Serotonin Antagonists pharmacology, Cell Degranulation, Syk Kinase metabolism, Receptors, IgE, Mast Cells, Leukemia
- Abstract
In the present study, we found that methiothepin (a nonselective 5-hydroxytryptamine [5-HT] receptor antagonist) inhibited antigen-induced degranulation in rat basophilic leukemia cells and mouse bone marrow-derived mast cells. Although antigen stimulation induces release of histamine and serotonin (5-HT) by exocytosis and mast cells express several types of 5-HT receptor, the detailed role of these receptors remains unclear. Here, pretreatment of cells with methiothepin attenuated increased intracellular Ca
2+ concentration, phosphorylated critical upstream signaling components (Src family tyrosine kinases, Syk, and PLCγ1), and suppressed TNF-α secretion via inhibition of Akt (a Ser/Thr kinase activated by PI3K)and ERK phosphorylation. Furthermore, it inhibited PMA/ionomycin-induced degranulation; this finding suggested that methiothepin affected downstream signaling. IκB kinase β phosphorylates synaptosomal associated protein 23, which regulates the fusion events of the secretory granule/plasma membrane after mast cell activation, resulting in degranulation. We showed that methiothepin blocked PMA/ionomycin-induced phosphorylation of synaptosomal associated protein 23 by inhibiting its interaction with IκB kinase β. Together with the results of selective 5-HT antagonists, it is suggested that methiothepin inhibits mast cell degranulation by downregulating upstream signaling pathways and exocytotic fusion machinery through mainly 5-HT1A receptor. Our findings provide that 5-HT antagonists may be used to relieve allergic reactions., (© 2023 Wiley-VCH GmbH.)- Published
- 2023
- Full Text
- View/download PDF