This project examines the properties of a new class of intracellular Ca channel formed by polycystin-2. To date two major classes of Ca release channel have been identified: the ryanodine receptor (RyR) and the inositol 1,4,5-trisphosphate receptor (InsP3R). Most cells contain both types of channel, but the relative densities vary dramatically. The co-existence of a variety of intracellular channels is not surprising as cells need to respond to diverse stimuli with specific responses. The hypotheses to be tested are: 1) Polycystin-2 is a unique calcium- permeable channel in the endoplasmic reticular membrane. 2) The calcium channel formed by polycystin-2 is regulated by intracellular factors, including magnesium, eicosanoids, cAMP and polycystin-1. 3) specific regions of the protein can be divided into functional domains. These domains are based upon mutations found in polycystin-2 from subsets or individuals affected with autosomal dominant polycystic kidney disease (ADPKD). 4) Changes in channel activity of polycystin-2 will modify intracellular calcium signaling. The preliminary results presented here show for the first time that polycystin-2 makes a novel calcium permeable channel in the endoplasmic membrane. The experiments outlined in this project will investigate the functional properties of polycystin-2 at the single channel level and will correlate the channel properties with cell and organ function. The results to be obtained will identify regulatory factors that may determine the mechanism of action of polycystin-2 at a molecular level and may suggest useful tretments for individuals affected with polycystic kidney disease.
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