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.
| Li, Ao; Tian, Xin; Zhang, Xiaoli et al. (2015) Human polycystin-2 transgene dose-dependently rescues ADPKD phenotypes in Pkd2 mutant mice. Am J Pathol 185:2843-60 |
| Merrick, David; Bertuccio, Claudia A; Chapin, Hannah C et al. (2014) Polycystin-1 cleavage and the regulation of transcriptional pathways. Pediatr Nephrol 29:505-11 |
| Cai, Yiqiang; Fedeles, Sorin V; Dong, Ke et al. (2014) Altered trafficking and stability of polycystins underlie polycystic kidney disease. J Clin Invest 124:5129-44 |
| Paavola, Jere; Schliffke, Simon; Rossetti, Sandro et al. (2013) Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy. J Mol Cell Cardiol 58:199-208 |
| Yuan, Shiaulou; Zhao, Lu; Sun, Zhaoxia (2013) Dissecting the functional interplay between the TOR pathway and the cilium in zebrafish. Methods Enzymol 525:159-89 |
| Parikh, Chirag R; Dahl, Neera K; Chapman, Arlene B et al. (2012) Evaluation of urine biomarkers of kidney injury in polycystic kidney disease. Kidney Int 81:784-90 |
| Kuo, Ivana Y; Ehrlich, Barbara E (2012) Ion channels in renal disease. Chem Rev 112:6353-72 |
| Yoshiba, Satoko; Shiratori, Hidetaka; Kuo, Ivana Y et al. (2012) Cilia at the node of mouse embryos sense fluid flow for left-right determination via Pkd2. Science 338:226-31 |
| ?eli?, Andjelka S; Petri, Edward T; Benbow, Jennifer et al. (2012) Calcium-induced conformational changes in C-terminal tail of polycystin-2 are necessary for channel gating. J Biol Chem 287:17232-40 |
| Takiar, Vinita; Mistry, Kavita; Carmosino, Monica et al. (2012) VIP17/MAL expression modulates epithelial cyst formation and ciliogenesis. Am J Physiol Cell Physiol 303:C862-71 |
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