(A) Salivary gland secretion was assessed in control nonirradiated mice and irradiated mice that received AdCMV–green fluorescent protein (GFP) or AdCMV-STIM1GFP in salivary glands 15 days after irradiation with saliva collection done at 30 days after irradiation (12 mice each with AdCMV-GFP or AdCMV-STIM1GFP). (B) Thapsigargin-mediated Ca2+ release and influx were measured in acini from control (220 acini from three mice), IR-AdCTL (210 acini from three mice), and IR-AdSTIM1 (200 acini from three mice) mice. (C) Quantitation of data from (B). **P < 0.01, comparing indicated value with IR-AdCTL (A and C). (D) Model showing the early consequences of radiation treatment and mechanisms underlying persistent loss of salivary secretion. Effects of irradiation (black arrows) lead to TRPM2 activation. TRPM2-mediated Ca2+ entry causes an increase in [Ca2+]mt and ROS, depolarization of ψm, and caspase-3 activation, which lead to loss of STIM1 (solid red arrows). Consequently, SOCE is reduced, which attenuates agonist-stimulated sustained increases in [Ca2+]i that are required to activated Ca2+-dependent ion channels that drive fluid secretion (red dashed arrows).