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1 The Johns Hopkins Division of Renal Medicine at The Bayview Medical Center, Baltimore, MD, USA
2 San Raffaele Scientific Institute, Dulbecco Telethon Institute (DTI) @Dibit 4A1, Milan, Italy
3 The Johns Hopkins Division of Renal Medicine at Johns Hopkins School of Medicine, Baltimore, MD, USA
4 The Division of Cardiology, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
* To whom correspondence should be addressed. E-mail: msutters{at}jhmi.edu.
Autosomal Dominant Polycystic Kidney Disease (ADPKD) types 1 and 2 arise as a consequence of mutations in the PKD 1 or PKD2 genes, encoding polycystins 1 and 2. Since loss of function of either of the polycystins leads to a very similar phenotype and the two proteins are known to interact, polycystins 1 and 2 are probably active in the same pathway. The way in which loss of either polycystin leads to the development of ADPKD remains to be established, but disturbances of cell calcium regulation are likely to play an important role. Here we demonstrate that polycystin-1, heterologously expressed in MDCK cells, had a pronounced effect on intracellular calcium homeostasis. ATP-induced calcium responses in transfection control cells exhibited a double peak and relatively gradual return to baseline. By contrast, cells expressing heterologous polycystin-1 showed a brief, uniphasic, peak and an accelerated rate of decay. Heterologously expressed polycystin-1 accelerated ER calcium re-uptake and inhibited capacitative calcium entry; we found no effect of the protein on mitochondrial calcium buffering or plasma membrane calcium extrusion. We therefore propose that polycystin-1 accelerated the decay of the cell calcium response to ATP by up-regulation of ER calcium re-uptake and consequent minimization of the stimulus for capacitative calcium entry. It is possible that cellular de-differentiation, fluid secretion and proliferation might therefore arise in ADPKD as a consequence of disturbances in cytoplasmic and ER calcium homeostasis and aberrant capacitative calcium entry.
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