Function of TRPC3 in salivary gland

TRPC3在唾液腺中的功能

• 批准号: 8240207
• 负责人: Bidhan Chandra Bandyopadhyay
• 金额: $ 4.17万
• 依托单位: INSTITUTE FOR CLINICAL RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240207
• 关键词: Function; TRPC3; salivary; gland

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.

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，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，并且被认为参与Na+等离子的重吸收。目前尚不清楚唾液腺管是否像外分泌胰管一样；由于唾液中的 [Ca2+] 含量较高，因此会重新吸收钙。一些早期的报告表明，唾液流经导管腔时，[Ca2+] 存在梯度下降。因此，我们认为唾液导管细胞可能会重吸收 Ca2+，因为维持钙水平对于维持唾液流过导管腔至关重要。此外，高唾液钙被认为是唾液腺结石或唾液石形成的一个促成因素。唾液管结石是唾液腺最常见的疾病，是由于钙浓度较高而形成主要成分为磷酸钙的唾液结石所致。值得注意的是，在肾脏等组织中，结石的形成与钙重吸收的变化有关。唾液腺管的钙重吸收是否参与调节唾液中的钙水平尚不清楚。 TRPC3 是一种 Ca2+ 进入通道，主要位于 SMG 导管的顶膜中。 CSR 是一种 G 蛋白偶联受体，也存在于唾液腺导管的同一区域，似乎与 TRPC3 相关。我们的中心假设是，腺泡细胞分泌的唾液中的钙在流经导管系统时会激活 CSR，从而可能通过 TRPC3 通道调节 Ca2+ 流入。这将导致跨上皮钙流穿过唾液导管细胞。我们建议这种唾液钙浓度的调节有助于保护唾液管免受钙结石形成。这项研究解决了唾液腺功能的一个未知方面，即钙重吸收。此外，从拟议研究中获得的数据将阐明唾液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动调节机制，可以防止导管阻塞导致的唾液腺功能障碍。因此，我们相信我们的概念是创新的，所提出的研究也是新颖的。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，而且还将揭示唾液结石所涉及的机制，这些机制可能应用于制定治疗策略。未来方向：目前的研究将有助于了解 TRPC3 在 Ca2+ 进入唾液腺导管细胞中的作用。这种 Ca2+ 流入可能是唾液腺导管细胞中 Ca2+ 重吸收的机制。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结石形成发展的细胞和分子基础，这将对预防唾液结石非常有帮助。此外，这项研究和未来的项目也将有助于确定针对上述临床病症开发新药的潜在候选者。 公共健康相关性： 唾液结石，即由于唾液管堵塞而在唾液管内形成结石，是最常见的唾液腺疾病。据估计，每 1000 名成年人中就有 12 人患有此病，占大唾液腺疾病的 50% 以上。目前的研究将有助于了解唾液结石所涉及的机制，这可能有助于制定治疗策略。这项研究非常重要，因为高唾液钙被认为是唾液石形成的一个促成因素。这项研究还解决了唾液腺功能的一个未知方面，即钙重吸收。此外，拟议的研究将阐明唾液管是否积极参与调节唾液质量。