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1 The Division of Renal Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA; Center for Nephrology, Royal Free and University College Medical School, London, United Kingdom; Department of Physiology/Autonomic Neuroscience Institute, Royal Free and University College Medical School, London, United Kingdom
2 The Division of Renal Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
3 Center for Nephrology, Royal Free and University College Medical School, London, United Kingdom; Department of Physiology/Autonomic Neuroscience Institute, Royal Free and University College Medical School, London, United Kingdom
4 The Division of pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
5 The Laboratory of Cardiological Sciences, Gerontology Research Center, Baltimore, MD, USA
6 Department of Physiology/Autonomic Neuroscience Institute, Royal Free and University College Medical School, London, United Kingdom
* To whom correspondence should be addressed. E-mail: msutters{at}jhmi.edu.
The precise steps leading from mutation of the 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 chloride 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 carboxyl terminus of polycystin-1 in stably transfected mouse cortical collecting duct cells. The truncated polycystin-1 fusion protein prolonged the duration of ATP-stimulated chloride conductance and intracellular calcium responses. Both effects were dependent upon extracellular calcium. It was determined that expression of the truncated polycystin-1 fusion protein introduced, or activated, an ATP-induced calcium 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 calcium homeostasis, and indicate that dysregulated calcium entry might promote chloride secretion and cyst expansion in ADPKD.
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