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TRANSLATIONAL PHYSIOLOGY
Divisions of 1Renal Medicine and 4Cardiology, Johns Hopkins Bayview Medical Center, and 3The Johns Hopkins School of Medicine, Baltimore, Maryland; and 2Department of Biological Research and Technology, Dulbecco Telethon Institute, San Raffaele Scientific Institute, Milan, Italy
Submitted 21 September 2004 ; accepted in final form 1 May 2005
Autosomal dominant polycystic kidney disease (ADPKD) types 1 and 2 arise as a consequence of mutations in the PKD1 or PKD2 genes, encoding polycystins-1 and -2. Because 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 Madin-Darby canine kidney 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 endoplasmic reticulum (ER) calcium reuptake 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 upregulation of ER calcium reuptake and consequent minimization of the stimulus for capacitative calcium entry. It is possible that cellular dedifferentiation, 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.
autosomal dominant polycystic kidney disease; purinergic; calcium signaling; stable transfection; Madin-Darby canine kidney cells
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