FUNCTION AND REGULATION OF POLYCYSTIN-2

本项目研究多囊蛋白-2(PC2)作为细胞内钙通道的特性。在这个项目中，将测试两类潜在的调节器，其中每个调节器都是综合体或级联的一部分。扰乱细胞内钙信号和随后的下游信号调节的后果将被测试。从这些实验中获得的结果将确定调节PC2活性的调控因子，将概述这些相互作用的分子基础以及它们是如何被调控的，并将为Siganling级联反应的下游目标提供建议。需要检验的假设是：1)PC1和PC2之间的相互作用是功能性的，可以从PC2的分子性质来预测。2)PC2和RyR形成通道复合体，其中PC2调节RyR的活性，RyR进而调节全球细胞内钙 发信号。3)通道复合体调节的改变将改变细胞内钙信号和完整细胞的下游信号。这些变化将对完好无损的动物的器官产生影响。这里提出的初步结果表明，PC2有几个蛋白质伙伴，这些相关蛋白质对调节通道复合体是重要的。本项目中概述的实验将在单通道水平上研究PC2的功能特性，并将通道特性与细胞和器官功能相关联。将获得的结果可能在分子水平上确定PC2的作用机制，并可能为多囊肾病患者提供有用的治疗方案。

This project examines the properties of polycystin-2 (PC2) as an intracellular calcium channel. In this project two classes of potential regulators will be tested where each regulator is part of the complex or cascade. The consequences of disrupting the regulation on the intracellular calcium signaling and on the subsequent downstream signaling will be tested. The results obtained from these experiments will identify regulatory factors that modulate the activity of PC2, will outline the molecular basis for these interactions and how they are regulated, and will suggest downstream targets for the siganling cascade. The hypotheses to be tested are: 1) The interactions between PC1 and PC2 are functional and can be predicted from the molecular properties of PC2. 2) PC2 and the ryanodine receptor (RyR) make a channel complex where PC2 regulates the activity of the RyR which then can modulate global intracellular calcium signaling. 3) Changes in the regulation of the channel complex will modify intracellular calcium signaling, and downstream signaling in intact cell. These changes will have consequences on organs in the intact animal. The preliminary results presented here show that PC2 has several protein partners and that these associated proteins are important for regulating the channel complex. The experiments outlined in this project will investigate the functional properties of PC2 at the single channel level and will correlate the channel properties with cell and organ function. The results to be obtained may determine the mechanism of action of PC2 at a molecular level and may suggest useful treatments for individuals affected with polycystic kidney disease.