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Mast cells (MCs) release pro-inflammatory mediators through a process called degranulation response. The latter may be induced by several conditions, including antigen recognition through immunoglobulin E (IgE) or “cross-linking,” classically associated with Type I hypersensitivity reactions. Early in this reaction, Ca 2+  influx and subsequent increase of intracellular free Ca 2+  concentration are essential for MC degranulation. Several membrane channels that mediate Ca 2+  influx have been proposed, but their role remains elusive. Here, we evaluated the possible contribution of pannexin-1 channels (Panx1 Chs), well-known as ATP-releasing channels, in the increase of intracellular Ca 2+  triggered during cross-linking reaction of MCs. The contribution of Panx1 Chs in the degranulation response was evaluated in MCs from wild type (WT) and Panx1 knock out (Panx1 −/− ) mice after anti-ovalbumin (OVA) IgE sensitization. Notably, the degranulation response (toluidine blue and histamine release) was absent in Panx1 −/−  MCs. Moreover, WT MCs showed a rapid and transient increase in Ca 2+  signal followed by a sustained increase after antigen stimulation. However, the sustained increase in Ca 2+  signal triggered by OVA was absent in Panx1 −/−  MCs. Furthermore, OVA stimulation increased the membrane permeability assessed by dye uptake, a prevented response by Panx1 Ch but not by connexin hemichannel blockers and without effect on Panx1 −/−  MCs. Interestingly, the increase in membrane permeability of WT MCs was also prevented by suramin, a P2 purinergic inhibitor, suggesting that Panx1 Chs act as ATP-releasing channels impermeable to Ca 2+ . Accordingly, stimulation with exogenous ATP restored the degranulation response and sustained increase in Ca 2+  signal of OVA stimulated Panx1 −/−  MCs. Moreover, opening of Panx1 Chs in Panx1 transfected HeLa cells increased dye uptake and ATP release but did not promote Ca 2+  influx, confirming that Panx1 Chs permeable to ATP are not permeable to Ca 2+ . These data strongly suggest that during antigen recognition, Panx1 Chs contribute to the sustained Ca 2+  signal increase via release of ATP that activates P2 receptors, playing a critical role in the sequential events that leads to degranulation response during Type I hypersensitivity reactions.

Pannexin-1 Channels Are Essential for Mast Cell Degranulation Triggered During Type I Hypersensitivity Reactions