Ablation of TRPC3 disrupts Ca2+ signaling in salivary ductal cells and promotes sialolithiasis.

Clinical studies and structural analyses of salivary stones strongly suggest a linkage between higher saliva calcium (Ca²⁺) and salivary stone formation, sialolithiasis; however, the process and the mechanism leading to Ca²⁺ overload during sialolithiasis is not well understood. Here, we show that TRPC3 null (−/−) mice presented with a reduction in Ca²⁺ entry and current in ductal cells with higher saliva [Ca²⁺] suggesting diminished transepithelial Ca²⁺ flux across the salivary ductal cells, leaving more Ca²⁺ 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 Ca²⁺ 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 [Ca²⁺], along with elevated detrimental gene expressions, altogether contributing to salivary gland stone formation. [ABSTRACT FROM AUTHOR]