*3.3. Dysregulated Calcium Signaling*

Intracellular calcium levels are tightly regulated and impact a multitude of signaling pathways, including induction of saliva secretion, and have been shown to be dysregulated following irradiation of SMGs [45,46]. Blocking activation of the calcium-permeable cation channel, TRPM2, by pharmacologically scavenging free radicals with Tempol or inhibiting PARP1 activity, attenuates ROS production and preserves salivary gland function at days 10–30 following administration of 15 Gy IR, which was also seen in TRPM2−/<sup>−</sup> mice [46]. Further evaluation of this pathway illustrated that TRPM2 activation and mitochondrial calcium uniporter (MCU) activity induced cleavage of the stromal interaction molecule 1 (STIM1) via caspase-3 activation within 48 h of IR exposure [45]. STIM1 function is necessary for regulating calcium stores in the endoplasmic reticulum and mediates store-operated calcium entry into acinar cells, with alterations in this pathway leading to reduced saliva secretion at day 30 post-IR. Blocking TRPM2, MCU or caspase-3 function with siRNA or pharmacological inhibitors reversed the hyposalivation phenotype. Likewise, adenovirus-induced expression of STIM1 at day 15 post-IR improved salivary gland function by day 30 following IR-induced damage [45]. These results suggest a key role for the regulation of intracellular calcium signaling in preserving salivary gland function post-IR.
