TRPC1, Calcium, and Saliva Secretion

项目摘要 唾液具有许多极其重要的生物功能，这些功能有助于维持口腔 健康。据估计，美国有500多万人患有唾液腺 功能障碍。唾液的分泌是由许多离子通道和转运体的协同活动驱动的。 虽然，钙被认为是调节液体分泌的主要细胞内因素，但 参与细胞内钙调节的分子机制尚不清楚。这主要是 由于缺乏关于唾液中存在的钙通道调节机制的信息 腺体。此外，细胞内钙的增加如何调节唾液，目前还没有相关信息。 分泌物。此外，在Sjögerns综合征患者中，尽管腺泡组织看起来正常，但它们确实是正常的 功能不正常，对激动剂刺激的钙反应降低。这一观察结果引发了 在这种病理状态下，钙通道可能发生改变。从我们的网站上获得的结果 获奖表明TRPC1是唾液腺的主要钙通道，并且与 涉及唾液分泌。为了了解TRPC1通道的调节，我们已经在人类 颌下腺细胞、TRPC1与STIM1、Cav1和Orai1的相互作用决定TRPC1介导 钙离子进入。此外，这些蛋白质之间的相互作用被限制在血浆中的特定区域。 然而，在唾液腺组织中是否也存在类似的机制，目前尚不清楚。 因此，在这次更新中，我们打算彻底描述唾液腺中胞浆钙的作用。 功能，并确定瞬时受体电位规范(TRPC1)-1与 唾液分泌物。这项研究的假设是，由于通过TRPC1的钙内流在 唾液腺的生理功能，唾液腺中钙通道的特征将是 重要的是要了解唾液分泌的机制，它可以代表唾液中的药物靶点。 腺体功能障碍。我们将协调我们的努力，以确定TRPC1的功能意义 调节唾液分泌的通道以及它如何导致唾液腺破坏。我们还将调查 脂筏在小鼠颌下腺细胞TRPC1通道组装/激活中的作用 并将确定通过STIM1和Orai1调控TRPC1的机制。我们的结果是 研究有望为钙通道的作用和分子机制提供新的见解 与唾液分泌有关。更多地了解这些导致唾液分泌的事件将是 对阐明唾液腺功能障碍的新疗法具有重要意义。

Project Summary Saliva performs a number of extremely important biological functions that are instrumental in maintaining oral health. It has been estimated that more than 5 million people in the US suffers from salivary gland dysfunction. Secretion of saliva is driven by concerted activities of a number of ion channels and transporters. Although, it is believed that calcium is the primary intracellular factor that regulates fluid secretion, the molecular mechanism involved in the regulation of cytosolic calcium is not clearly understood. This is primarily due to the lack of information regarding the mechanism of regulation of calcium channels present in salivary glands. Furthermore, no information is available as how increase in cytosolic calcium modulates saliva secretion. Moreover, in Sjögerns syndrome patients, although the acinar tissues appear to be normal, they do not function properly and have a decreased calcium response to agonist-stimulation. This observation raises the possibility that calcium channels might be altered in this pathological condition. Results obtained from our awarded grant indicate that TRPC1 is the primary calcium channel in salivary glands and is intimately involved saliva secretion. To understand the regulation of TRPC1 channel we have shown that in human submandibular gland cells, TRPC1 interaction with STIM1, Cav1, and Orai1 dictates TRPC1 mediated calcium entry. Furthermore, these protein-protein interactions were confined to specific domains in the plasma membrane, however nothing is known if similar mechanisms are also present in vivo in salivary gland tissues. Therefore, in this renewal we intend to thoroughly characterize the role of cytosolic calcium in salivary gland function and to determine the relationship between transient receptor potential canonical (TRPC1) -1 and saliva secretion. The hypothesis of this study is that because calcium influx via TRPC1 plays a pivotal role in the physiological function of salivary glands, characterization of calcium channels in salivary glands will be important to understand the mechanism of saliva secretion, which could represent as drug targets in salivary gland dysfunction. We will coordinate our efforts in order to determine the functional significance of TRPC1 channel in regulating saliva secretion and how it leads to salivary gland destruction. We will also investigate the role of lipid rafts in the assembly/activation of the TRPC1 channel in mouse submandibular gland cells and will identify the mechanism involved in the regulation of TRPC1 via STIM1 and Orai1. The results of our studies are expected to provide new insights into the role of calcium channels and the molecular mechanism involved in saliva secretion. Greater understanding of these events responsible for saliva secretion will be important in elucidating new therapy for salivary gland dysfunctions.