TRPC1, Calcium, and Saliva Secretion

项目摘要 唾液是维持口腔健康的几种生物功能所必需的。它有 据估计，美国有500多万人患有唾液腺功能障碍。虽然 唾液分泌是由几个离子通道和转运体的协同活动驱动的，分子 刺激唾液分泌的机制尚不清楚。有人建议， Ca~(2+)在调节体液分泌方面起着中心作用；然而，有关 唾液腺中的钙通道及其调节机制尚不清楚。 明白了。此外，在唾液腺功能障碍方面，如原发性干燥综合征(PSS)患者 腺泡组织看起来正常，但功能不正常，钙反应减弱。 对激动剂的刺激。这一观察结果提出了在这种情况下钙离子通道可能发生改变的可能性 病理状态。结果表明，TRPC1是主要的钙离子。 唾液腺中的经络与唾液分泌密切相关。要了解规则的规则 TRPC1通道我们已经证明，TRPC1是通过复杂的蛋白质-蛋白质相互作用来调节的。 此外，这些相互作用仅限于质膜中的特定区域，但蛋白质 目前尚不清楚是什么支撑了这些复合体。因此，在这次更新中，我们打算彻底描述 细胞内钙离子在唾液腺功能中的作用及TRPC1与唾液腺功能的关系 唾液腺功能失调。这一竞争性更新的目的是阐明钙信号转导。 S在涎腺功能障碍中的作用机制，并确定TRPC1在PSS中的作用。此次续订 应用是基于这样的假设，即TRPC1介导的钙内流的丧失诱导内质网应激， 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和涉及的分子机制提供新的见解 唾液腺功能障碍以及恢复唾液腺功能的方法。更好地理解 这些事件将对阐明唾液腺功能障碍的新疗法具有重要意义。

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.