The isolated polycystin-1 cytoplasmic COOH terminus prolongs ATP-stimulated Cl^- conductance through increased Ca²⁺ entry

The precise steps leading from mutation of the polycystic kidney disease (PKD1) gene to the autosomal dominant polycystic kidney disease (ADPKD) phenotype remain to be established. Fluid accumulation is a requirement for cyst expansion in ADPKD, suggesting that abnormal fluid secretion into the cyst lumen might play a role in disease. In this study, we sought to establish a link between polycystin-1 (the PKD1 gene product) and ATP-stimulated Cl ^- secretion in renal tubule cells. To do this, we performed a whole cell patch-clamp analysis of the effects of expression of the isolated cytoplasmic COOH-terminus of polycystin-1 in stably transfected mouse cortical collecting duct cells. The truncated polycystin-1 fusion protein prolonged the duration of ATP-stimulated Cl^- conductance and intracellular Ca ²⁺ responses. Both effects were dependent on extracellular Ca ²⁺. It was determined that expression of the truncated polycystin-1 fusion protein introduced, or activated, an ATP-induced Ca²⁺ entry pathway that was undetectable in transfection control cell lines. Our findings are concordant with increasing evidence for a role of polycystin-1 in cell Ca²⁺ homeostasis and indicate that dysregulated Ca²⁺ entry might promote Cl^- secretion and cyst expansion in ADPKD.