Deletion of Orai2 augments endogenous CRAC currents and degranulation in mast cells leading to enhanced anaphylaxis

• Verfasst von: Tsvilovskyy, Volodymyr [VerfasserIn]
• Verfasst von: Solís López, Alejandra [VerfasserIn]
• Verfasst von: Schumacher, Dagmar [VerfasserIn]
• Verfasst von: Medert, Rebekka [VerfasserIn]
• Verfasst von: Roers, Axel [VerfasserIn]
• Verfasst von: Kriebs, Ulrich [VerfasserIn]
• Verfasst von: Freichel, Marc [VerfasserIn]
• Titel: Deletion of Orai2 augments endogenous CRAC currents and degranulation in mast cells leading to enhanced anaphylaxis
• Verf.angabe: Volodymyr Tsvilovskyy, Alejandra Solís-López, Dagmar Schumacher, Rebekka Medert, Axel Roers, Ulrich Kriebs, Marc Freichel
• Jahr: 2018
• Jahr des Originals: 2017
• Umfang: 10 S.
• Fussnoten: Published online 27 November 2017 ; Gesehen am 14.06.2019 ; Available online 27 November 2017
• Titel Quelle: Enthalten in: Cell calcium
• Ort Quelle: Edinburgh [u.a.] : Churchill Livingstone, 1980
• Jahr Quelle: 2018
• Band/Heft Quelle: 71(2018), Seite 24-33
• ISSN Quelle: 1532-1991
• DOI: doi:10.1016/j.ceca.2017.11.004
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Antigen
• Sach-SW: Beta-hexosaminidase
• Sach-SW: Calcium
• Sach-SW: Chloroquine
• Sach-SW: Compound 48/80
• Sach-SW: CRAC current
• Sach-SW: Knock-out
• Sach-SW: Mast cell activation
• Sach-SW: MRGPRB2
• Sach-SW: ORAI2
• Sach-SW: Store-operated Ca entry
• Sach-SW: Systemic anaphylaxis
• K10plus-PPN: 1667447300

Abstract

All three members of the Orai family of cation channels-Orai1, Orai2 and Orai3-are integral membrane proteins that can form store-operated Ca2+ channels resembling endogenous calcium release-activated channels (CRAC) in many aspects. Loss of function studies in human and murine models revealed many functions of Orai1 proteins not only for Ca2+ homeostasis, but also for cellular and systemic functions in many cell types. By contrast, the knowledge regarding the contribution of Orai2 and Orai3 proteins in these processes is sparse. In this study, we report the generation of mouse models with targeted inactivation of the Orai2 gene to study Orai2 function in peritoneal mast cells (PMC), a classical cell model for CRAC channels and Ca2+-dependent exocytosis of inflammatory mediators. We show that the Ca2+ rise triggered by agonists acting on high-affinity Fc receptors for IgE or on MAS-related G protein-coupled receptors is significantly increased in Orai2-deficient mast cells. Ca2+ entry triggered by depletion of intracellular stores (SOCE) is also increased in Orai2−/− PMCs at high (2mM) extracellular Ca2+ concentration, whereas SOCE is largely reduced upon re-addtion of lower (0.1mM) Ca2+ concentration. Likewise, the density of CRAC currents, Ca2+-dependent mast cell degranulation, and mast cell-mediated anaphylaxis are intensified in Orai2-deficient mice. These results show that the presence of Orai2 proteins limits receptor-evoked Ca2+ transients, store-operated Ca2+ entry (SOCE) as well as degranulation of murine peritoneal mast cells but also raise the idea that Orai2 proteins contribute to Ca2+ entry in connective tissue type mast cells in discrete operation modes depending on the availability of calcium ions in the extracellular space.