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This Article Full Text Full Text (PDF) All Versions of this Article: 285/6/F1168    most recent 00171.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Wildman, S. S. Articles by Sutters, M. Search for Related Content PubMed PubMed Citation Articles by Wildman, S. S. Articles by Sutters, M.

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

⁵Laboratory of Cardiological Sciences, Gerontology Research Center, Division of ¹Renal Medicine, Johns Hopkins Bayview Medical Center, and ⁴Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland 21224; and ²Center for Nephrology and ³Department of Physiology/Autonomic Neuroscience Institute, Royal Free and University College Medical School, University College London, London, W1T 3AA United Kingdom

Submitted 1 May 2003 ; accepted in final form 28 July 2003

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 Ca²⁺ responses. Both effects were dependent on extracellular Ca²⁺. 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.

autosomal dominant polycystic kidney disease; purinergic P₂ receptors; chloride channels; kidney collecting tubules; patch-clamp techniques

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