TRPC1, Calcium, and Saliva Secretion

项目摘要 唾液对维持口腔健康的几种生物功能至关重要。它有 据估计，美国有超过500万人患有唾液腺功能障碍。虽然 唾液分泌由几种离子通道和转运蛋白的协同活动驱动， 参与刺激唾液分泌的机制尚不清楚。有人建议 Ca 2+在调节体液分泌中起着核心作用，然而，关于细胞的身份的信息， 唾液腺中钙通道及其调节机制的研究尚不清楚 明白此外，在唾液腺功能障碍，如原发性干燥综合征（pSS）患者中， 腺泡组织看起来是正常的，但不能正常地发挥功能， 激动剂刺激。这一观察结果提出了一种可能性，即在这种情况下，Ca 2+通道可能会改变。 病理状态从我们获得的资助获得的结果表明，TRPC 1是主要的Ca 2 + 在唾液腺中的通道，并密切参与唾液分泌。为了了解 TRPC 1通道，我们已经表明，TRPC 1是通过一个复杂的蛋白质-蛋白质相互作用的调节。 此外，这些相互作用仅限于质膜中的特定区域，但蛋白质 锚定这些复合物的机制尚不清楚。因此，在这次更新中，我们打算彻底描述 胞浆Ca 2+在唾液腺功能中的作用，并确定TRPC 1与 唾液腺功能障碍这种竞争性更新的目的是阐明Ca 2+信号转导 唾液腺功能障碍的机制，并建立TRPC 1在pSS中的作用。此续订 本申请基于以下假设：TRPC 1介导的Ca 2+内流的丧失诱导ER应激， 促进免疫渗透，导致唾液腺破坏。我们的研究结果是 有望为钙通道的作用及其分子机制提供新的见解 唾液腺功能障碍以及恢复功能性唾液腺的方法。更好地了解 这些事件在阐明唾液腺功能障碍的新疗法中将是重要的。

Project Summary Saliva is essential for several 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. Although saliva secretion is driven by concerted activities of several ion channels and transporters, the molecular mechanism involved in stimulated saliva secretion is not clearly understood. It has been suggested that Ca2+ plays a central role that regulates fluid secretion; however, information regarding the identity of the Ca2+ channels as well as the mechanism of regulation of these channels in salivary glands is not well understood. Moreover, in salivary gland dysfunction, such as primary Sjogren's syndrome (pSS) patients the acinar tissues appear to be normal but fail to function properly and have a decreased calcium response to agonist-stimulation. This observation raises the possibility that Ca2+ channels might be altered in this pathological condition. Results obtained from our awarded grant indicate that TRPC1 is the primary Ca2+ channel in salivary glands and is intimately involved saliva secretion. To understand the regulation of TRPC1 channel we have shown that TRPC1 is regulated through a complex protein-protein interaction. Furthermore, these interactions were confined to specific domains in the plasma membrane, but the protein that anchors these complexes is not clear. Therefore, in this renewal we intend to thoroughly characterize the role of cytosolic Ca2+ in salivary gland function and to determine the relationship between TRPC1 and salivary gland dysfunctions. The objective of this competitive renewal is to elucidate the Ca2+ signaling mechanism(s) in salivary gland dysfunction and establish the role of TRPC1 in pSS. This renewal application is based on the hypothesis that loss of TRPC1-mediated Ca2+ influx induces ER stress, promotes immune infiltration that leads to salivary gland destruction. The results of our studies are expected to provide new insights into the role of calcium channels and the molecular mechanism involved in salivary gland dysfunction as well as ways to restore functional salivary glands. Greater understanding of these events will be important in elucidating new therapy for salivary gland dysfunctions.