Store-operated Ca2+ entry mediated by STIM1 and STIM2 regulates salivary secretion and KCa channels in salivary gland.

Salivary gland fluid secretion is primarily regulated by intracellular calcium levels ([Ca2+]i). A key mechanism for sustaining elevated [Ca2+]i is store-operated Ca2+ entry (SOCE) initiated by the endoplasmic reticulum (ER)-resident proteins STIM1 and STIM2. This study aims to determine the in vivo role of SOCE mediated by STIM1 and STIM2 in salivary secretion and investigate its downstream effects on Ca2+-activated potassium (KCa) channels. Epithelium-specific conditional knockout mice for Stim1 and Stim2 (Stim1/2 cKO) were generated, and pilocarpine-stimulated salivary secretions in Stim1/2 cKO mice and control mice (Stim1/2fl/fl) were measured. The Stim1/2 cKO mice exhibited a significant reduction in salivary secretion compared with the control group, with no discernible changes in protein, Ca2+, and K+ concentrations in the saliva. In addition, the effects of Stim1/2 deletion on [Ca2+]i dynamics and KCa channel activation were examined using Fura-2 fluorescence and a potassium flux assay, respectively, in isolated acinar cell clusters from the mouse submandibular gland. In these cells, the initial release of Ca2+ from ER stores was comparable between genotypes following carbachol stimulation. However, the sustained influx of Ca2+ via SOCE was significantly reduced in Stim1/2 cKO cells, mediated by the ORAI1 channel. The gene expression levels of KCa1.1 and KCa3.1 remained unchanged; however, KCa channel activity was significantly diminished in Stim1/2 cKO cells, similar to the effects of KCa channel inhibitors. These findings indicate that the loss of SOCE decreases the [Ca2+]i and intracellular Ca2+ signals required for salivary secretion, possibly through the ORAI1 channel, in turn reducing KCa channel activation.