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.