*4.1. ATP Release*

In addition to responding to elevated eATP, the P2X7 receptor (P2X7R) has been implicated in the IR-induced release of ATP. As previously described in B16 murine melanoma cells [124], we recently demonstrated that γ-irradiation of parotid epithelial cells induces release of eATP in a P2X7R-dependent manner [48]. One way that IR induces the release of eATP is through upregulation of connexin 43 (Cx43) [140], a gap junction hemichannel involved in intercellular communication [141], as well as eATP release [142,143]. The activation of P2X7R by eATP induces an increase in the cytoplasmic calcium concentration, [Ca2<sup>+</sup>]i, which promotes eATP release via Cx43 [128]. Indeed, Cx43-mediated

release of ATP following irradiation of B16 melanoma cells is dependent on P2X7R [123]. As reported, IR-induced ATP release through Cx43 could be suppressed by blockade of P2X7R or downstream purinergic signaling pathways, including tyrosine kinase and Rho kinase activation, actin cytoskeletal rearrangements and increases in [Ca2<sup>+</sup>]i and ROS production [123]. Together, these data demonstrate a role for P2X7R in mediating release of eATP following IR.
