Ablation of TRPC3 disrupts Ca 2+ signaling in salivary ductal cells and promotes sialolithiasis.

Clinical studies and structural analyses of salivary stones strongly suggest a linkage between higher saliva calcium (Ca ²⁺ ) and salivary stone formation, sialolithiasis; however, the process and the mechanism leading to Ca ²⁺ overload during sialolithiasis is not well understood. Here, we show that TRPC3 null (-/-) mice presented with a reduction in Ca ²⁺ entry and current in ductal cells with higher saliva [Ca ²⁺ ] suggesting diminished transepithelial Ca ²⁺ flux across the salivary ductal cells, leaving more Ca ²⁺ in ductal fluid. Significantly, we found that TRPC3 was expressed in mice and human salivary ductal cells, while intraductal stones were detected in both mice (TRPC3 ^-/- ) and patient (sialolithiasis) salivary glands. To identify the mechanism, we found that TRPC3 was crucial in preventing the expression of calcification genes (BMP2/6, Runx2) in ductal cells which may be due to higher extracellular Ca ²⁺ in SMG tissues. Similarly, inflammatory (IL6, NLRP3), fibrotic (FN1, TGFβ1) and apoptotic (Bax1/Bcl2) markers were also elevated, suggesting that the loss of TRPC3 induces genetic changes that leads to salivary gland cell death and induction of inflammatory response. Overall, ablation of TRPC3 ^-/- leads to higher saliva [Ca ²⁺ ], along with elevated detrimental gene expressions, altogether contributing to salivary gland stone formation.
(© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)