Regulatory Mechanism of Mast Cell Activation by Zinc Signaling

Mast cells are hematopoietic-lineage cells that participate in immunoglobulin E (IgE)-associated immune responses, including allergic reactions and parasite resistance. Recent studies have shown that zinc (Zn) ion can behave as an intracellular signaling molecule and that Zn is involved in mast cell activation. We demonstrated that mast cells stimulated through the high-affinity IgE receptor (FcεRI) rapidly release intracellular Zn from the endoplasmic reticulum (ER), and we named this phenomenon the "Zn wave". Furthermore, we found that the L-type calcium channel (LTCC) is the gatekeeper for the Zn wave. LTCC antagonists inhibited the Zn wave, and an agonist was sufficient to induce it. Notably, LTCC was mainly localized to the ER rather than to the plasma membrane in mast cells, and the Zn wave was impaired by LTCC knockdown. We also found that the LTCC-mediated Zn wave positively controlled inflammatory cytokine gene induction by enhancing the DNA-binding activity of nuclear factor-kappa B (NF-κB). These findings indicated that the LTCC has a novel function as a gatekeeper for the Zn wave, which is involved in regulating NF-κB signaling. In this review, we describe our current understanding of Zn signaling, especially with regard to the Zn wave and the role of Zn signaling in mast cells.