PROJECT SUMMARY Ion channels control such diverse processes as fertilization, proliferation, development, learning and memory. Ion channels are multispan transmembrane proteins that transport ~106 to 107 ions per second across membranes. Precise spatial and temporal regulation of ionic flux is the fundamental principle by which ion channels control such a diverse array of signaling modalities. Spatial regulation is achieved by targeting channels to subcellular compartments ensheathed in membranes such as the endoplasmic reticulum (ER) or endosomes, whereas temporal regulation by specific signals controlling opening and closing of channels. The primary cilium is an antenna-shaped protrusion from the apical plasma membrane and are enriched in a specific subset of ion channels called polycystins. Mutations in polycystins cause Autosomal Dominant Polycytsic Kidney Disease (ADPKD), which manifests in cyst formation in kidney and other organs, such as liver and pancreas. The molecular mechanisms by which polycystin channels are spatially and temporally regulated and thus contribute to ciliary signaling cascades still remain poorly understood. The central goal of this project is to understand the fundamental mechanisms at the molecular and cellular level by which polycystin channels are activated in primary cilia. There are three specific aims. The first aim defines the molecular motifs in PC1 and PC2 underlying the temporal regulation of the ciliary polycystin channel complex. The second aims defines the local regulation of polycystins by ciliary calcium levels. The third aim determine the physiological role of ciliary lipids in restricting polycystin activity to primary cilia. This proposal includes preliminary observations of two applicants with complementary expertise on polycystin channel function. Completion of this project will be a critical step towards understanding the fundamental principles of polycystin channel signaling within primary cilia. Our long‐term goal is to understand how dysregulation of polycystin channels causes ADPKD.