*4.2. Dysregulated Calcium Signaling*

Once released, eATP can then bind available P2 receptors, such as P2X7Rs or P2Y2Rs, and promote a host of signaling processes. As we discussed earlier, a rapid increase in [Ca2<sup>+</sup>]i is observed following irradiation of submandibular glands in mice via store-operated Ca2<sup>+</sup> entry (SOCE), a response that was abrogated in TRMP2-/- mice [45]. Activation of either P2X7R or P2Y2R by eATP leads to elevated [Ca2<sup>+</sup>]i though by different mechanisms. Like TRPM2, P2Y2Rs promote cytoplasmic entry of Ca2<sup>+</sup> via SOCE [144], while P2X7Rs mediate extracellular Ca2<sup>+</sup> influx [138]. Calcium signaling contributes to many of the signaling processes underlying bystander responses [145–147] that we will discuss in more detail below, including MAPK signaling [148], ROS production [146], NF-κB-mediated iNOS synthesis [149] and COX-2/PGE2 signaling [149–152]. A rapid increase in [Ca2<sup>+</sup>]i was observed in bystander cells that were exposed to conditioned medium (CM) from irradiated human keratinocytes [146], glioma and fibroblasts [148]. In human keratinocytes, the apoptosis observed in bystander cells following exposure to CM was blocked by treatment with the calcium chelator, EGTA, suggesting influx, not SOCE, was important for the observed bystander effect [146]. Because of the central role of Ca2<sup>+</sup> signaling in mediating bystander effects, the contributions of P2 receptors to IR-induced increases in [Ca2<sup>+</sup>]i following irradiation of the salivary gland should be further investigated.
