Extracellular Ca2+ aggravates IgE-induced allergic reaction in mast cells through GPRC6A, a novel family C G-protein-coupled receptor

Aims:As an essential indicator of allergic reactions, mast cell (MC) activation involves FcεRI-mediated signaling and the release of allergic mediators. In FcεRI signaling, Ca²⁺ is located at the intersection of multiple cellular signaling pathways. However, the effect of extracellular Ca²⁺ (exCa²⁺) on MCs during anaphylaxis remains unclear, along with its exact mechanisms. Therefore, we sought to determine whether and how elevated exCa²⁺ amplifies allergic reactions.

Main methods:In vitro experiments used immunoglobulin E (IgE)/antigen (Ag)-induced activation of rat and mouse MCs in vitro. The levels of MC degranulation mediators were used to evaluate the effect of exCa²⁺. In vivo experiments used MC-mediated passive systemic anaphylaxis (PCA) Balb/c mice. After stimulation, anaphylaxis indexes such as rectal temperature and allergic symptom score were detected.

Key findings:In vitro experiments revealed that exCa²⁺ is a stimulus signal for the aggravation of allergic reactions in MCs. When antagonists or siRNA inhibited GPRC6, MCs released fewer inflammatory mediators. Moreover, in vivo experiments confirmed in vitro results. Allergic symptoms were alleviated by antagonists NPS2143 in PCA mice, demonstrating that exCa²⁺ aggravates allergic reactions through GPRC6A.

Significance:Our study provides an essential theoretical basis for targeting Ca²⁺ and GPRC6A as therapeutic options for allergies.

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