Function of TRPC3 in salivary gland

描述（由申请人提供）：唾液腺腺泡细胞分泌高水平的钙以及唾液蛋白和液体。然后，这些唾液沿着导管系统向下流动，直到到达口腔。唾液管具有最小的分泌功能，并被认为参与离子如Na+的重吸收。目前尚不清楚是否唾液腺导管，如外分泌胰管；重新吸收钙，因为唾液中的[Ca2+]很高。一些早期的报道表明，当唾液流过导管腔时，唾液中的[Ca2+]有一个梯度下降。因此，我们提出唾液导管细胞可能会重新吸收Ca2+，因为维持钙水平对于维持通过导管腔的唾液流动至关重要。此外，高唾液钙被认为是唾液腺结石或唾液石形成的一个因素。唾液腺管结石是唾液腺最常见的疾病，主要是由于钙浓度较高而形成以磷酸钙为主的唾液腺结石。值得注意的是，在肾等组织中，结石的形成与钙重吸收的变化有关。唾液中钙的再吸收是否通过唾液腺导管调节尚不清楚。钙离子进入通道TRPC3主要位于SMG导管的顶端膜上。g蛋白偶联受体CSR也存在于唾液腺导管的同一区域，在那里它似乎与TRPC3相关。我们的中心假设是，从腺泡细胞分泌的唾液中的钙激活CSR，同时通过导管系统流动，可能通过TRPC3通道调节Ca2+内流。这将导致经上皮钙通量通过唾液导管细胞。我们认为这种唾液钙浓度的调节有助于保护唾液管免受钙结石的形成。这项研究解决了唾液腺功能的一个未知方面，即钙的重吸收。此外，从本研究中获得的数据将阐明唾液导管是否积极参与调节唾液质量。最后，研究结果还将揭示唾液腺是否具有固有的自我调节机制，以防止唾液腺因导管阻塞而功能障碍。因此，我们认为我们的概念是创新的，提出的研究是新颖的。从这项研究中获得的信息不仅有助于了解导管细胞功能的基本方面，而且还将揭示涎石症的机制，这可能有助于开发治疗策略。未来方向：本研究将有助于了解TRPC3在Ca2+进入唾液导管细胞中的作用。这种Ca2+内流可能是唾液导管细胞Ca2+重吸收的一种机制。基于这项研究的结果，我们将建立一个更大的项目来了解钙石形成的细胞和分子基础，这将对预防唾液石症非常有帮助。此外，本研究和未来的项目也将有助于确定潜在的候选药物来开发针对上述临床病症的新药。

DESCRIPTION (provided by applicant): Salivary gland acinar cells secrete high levels of calcium together with salivary proteins and fluids. This saliva then travels down the ductal system till it reaches the oral cavity. Salivary ducts have minimal secretory function and are proposed to be involved in reabsorption of ions such as Na+. It is presently unclear whether salivary gland ducts, like exocrine pancreatic ducts; reabsorb calcium since [Ca2+] in saliva is high. Some earlier reports show that there is a gradient in decrease in [Ca2+] in the saliva while flowing though the ductal lumen. Therefore we propose that salivary ductal cells might reabsorb Ca2+ since maintaining the calcium levels is essential for the maintenance of salivary flow through the ductal lumen. Furthermore, high saliva calcium has been suggested to be a contributing factor to the salivary gland stone formation or sialoliths. Stone formation in salivary duct is the most common disease of salivary glands that is caused by the formation of salivary calculi consisting of mainly calcium phosphate due to the presence of higher concentration of calcium. It is important to note that in tissues such as kidney, stone formation is associated with changes in calcium reabsorption. Whether calcium reabsorption via salivary gland ducts is involved in modulating calcium levels in saliva is not yet known. TRPC3, a Ca2+ entry channel is predominantly localized in apical membrane in the ducts of the SMG. CSR, a G-protein coupled receptor is also present in the same region of salivary gland ducts where it appears to associate with TRPC3. Our central hypothesis is that calcium in saliva secreted from acinar cells activates the CSR while flowing through the ductal system that potentially modulate the Ca2+ influx via TRPC3 channel. This would result in transepithelial calcium flux across the salivary ductal cell. We suggest that such regulation of saliva calcium concentration serve to protect salivary duct from calcium stone formation. This research addresses an as yet unknown aspect of salivary gland function, i.e. calcium reabsorption. Furthermore, data obtained from the proposed study will elucidate whether salivary ducts are actively involved in regulating the quality of saliva. Finally, the findings will also reveal whether salivary glands have inherent autoregulatory mechanisms, which prevent salivary gland dysfunction due to ductal obstructions. Thus we believe our concept is innovative and the proposed research is novel. Information gained from this study will not only help understanding basic aspects of ductal cell function but will also reveal mechanisms involved in sialolithiasis that could be potentially applied in development of therapeutic strategies. Future direction: Present study will help to understand the role of TRPC3 in Ca2+ entry into the salivary ductal cells. This Ca2+ influx could be a mechanism of Ca2+ reabsorption in salivary ductal cells. Based on the results obtained from this study, we will build up a bigger project to understand the cellular and molecular basis of the development of calcium stone formation and this will be extremely helpful to prevent sialolithiasis. Furthermore, this study and the future project will also help to identify the potential candidates to develop new drugs for the above clinical condition. Public Health Relevance: Sialolithiasis, stone formation in salivary duct due to blockage of salivary duct is the most common disease of salivary glands. It is estimated to affect 12 in 1000 of the adult population and accounts for more than 50% of diseases of the large salivary glands. Present study will help to understand the mechanisms involved in sialolithiasis that could be potentially applied in development of therapeutic strategies. This research is very important since high saliva calcium has been suggested to be a contributing factor to the formation of sialoliths. This research also addresses an as yet unknown aspect of salivary gland function, i.e. calcium reabsorption. Additionally, the proposed study will elucidate whether salivary ducts are actively involved in regulating the quality of saliva.