Radiation inhibits salivary gland function by promoting STIM1 cleavage by caspase-3 and loss of SOCE through a TRPM2-dependent pathway

Abstract

Store-operated Ca2+ entry (SOCE) is critical for salivary gland fluid secretion. We report that radiation treatment caused persistent salivary gland dysfunction by activating a TRPM2-dependent mitochondrial pathway, leading to caspase-3–mediated cleavage of stromal interaction molecule 1 (STIM1) and loss of SOCE. After irradiation, acinar cells from the submandibular glands of TRPM2+/+, but not those from TRPM2−/− mice, displayed an increase in the concentrations of mitochondrial Ca2+ and reactive oxygen species, a decrease in mitochondrial membrane potential, and activation of caspase-3, which was associated with a sustained decrease in STIM1 abundance and attenuation of SOCE. In a salivary gland cell line, silencing the mitochondrial Ca2+ uniporter or caspase-3 or treatment with inhibitors of TRPM2 or caspase-3 prevented irradiation-induced loss of STIM1 and SOCE. Expression of exogenous STIM1 in the salivary glands of irradiated mice increased SOCE and fluid secretion. We suggest that targeting the mechanisms underlying the loss of STIM1 would be a potentially useful approach for preserving salivary gland function after radiation therapy.

Differential regulation of ion channels function by proteolysis

“…This process is termed store operated Ca 2+ entry (SOCE) [25]. Calpain, γ-secretase and casepase-3 can cleave STIM1 thus regulating SOCE [21, 22, 26]. The Michalak group reported that calpain dynamically regulated STIM1 turnover and consequently SOCE through proteolysis of STIM1 proteins in both basal and apoptotic conditions.…”

“…In addition, it has been shown that in submandibular gland acinar cells, exposure to ionizing radiation led to caspase-3 activation and consequently STIM1 cleavage through a TRPM2-dependent pathway. Proteolysis of STIM1 further resulted in a marked loss of SOCE, and consequently decrease in fluid secretion [26]. In summary, proteolytic fragmentation of STIM1 by calpain, γ-secretase and caspase-3 regulates the amount of functional STIM1 on the ER membrane and hence the extent of Ca 2+ influx via the SOCE mechanism.…”

TRPM2‐mediated extracellular Ca2+ entry promotes acinar cell necrosis in biliary acute pancreatitis

“…As TRPM2 has been reported to induce mitochondrial damage (Liu et al . ), the mitochondrial membrane potential was measured (ΔΨ m ) in WT and TRPM2 pancreatic acinar cells. Administration of 1 m m H 2 O 2 resulted in a marked drop of ΔΨ m in WT cells (Fig.…”

“…These changes led to a sustained decrease in STIM1 expression and consequently decreased the store‐operated Ca 2+ entry (Liu et al . ).…”

“…In a downstream study, the authors also showed that irradiation activated a TRPM2‐dependent mitochondrial pathway, leading to caspase‐3 activation and mediated cleavage of stromal interaction molecule 1, which then attenuated store‐operated Ca 2+ entry (Liu et al . ). In the endocrine pancreas, TRPM2 has been suggested to play a role in diabetic stress‐induced mitochondrial fragmentation.…”