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.
journal_name
Sci Signaljournal_title
Science signalingauthors
Liu X,Gong B,de Souza LB,Ong HL,Subedi KP,Cheng KT,Swaim W,Zheng C,Mori Y,Ambudkar ISdoi
10.1126/scisignal.aal4064subject
Has Abstractpub_date
2017-06-06 00:00:00issue
482eissn
1945-0877issn
1937-9145pii
10/482/eaal4064journal_volume
10pub_type
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