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

Abstract

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.

• Authors: Bok-Eum Choi, Samuel Shin, Sade Evans, Brij B Singh, Bidhan C Bandyopadhyay
• Journal: Scientific reports (Sci Rep) Vol. 13 Issue 1 Pg. 5772 (04 08 2023) ISSN: 2045-2322 [Electronic] England
• PMID: 37031239 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Topics

• Humans
• Mice
• Animals
• Salivary Gland Calculi (genetics, surgery)
• Salivary Ducts
• Signal Transduction
• Saliva
• Cell Line