Journal
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
Volume 27, Issue 6, Pages 715-726Publisher
KARGER
DOI: 10.1159/000330080
Keywords
Polycystic Kidney Disease (ADPKD); Cyst; Calcium; PI3K/Akt; Polycystin-1; Polycystin-2; IP3R; STIM1
Categories
Funding
- National Institutes of Health [DK32753]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK090868, R01DK032753, R37DK032753] Funding Source: NIH RePORTER
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Dysregulation of Ca2+ signaling and homeostasis has been linked to the development of ADPKD through aberrant functioning of the polycystins. In this study, we investigated the role of the polycystins in modulating Ca2+ signaling. Expression of full-length PC1 in MDCK cells inhibited intracellular Ca2+ release in response to ATP when compared to control cells. This phenotype correlated with reduced interaction of endogenous PC2 and IP3R in PC1-containing cells. We also found that endogenous STIM1 also interacted with the IP3R, and this interaction was enhanced by PC1 expression. Increased interaction between STIM1 and IP3R inhibited Ca2+ release. PC1 regulates intracellular Ca2+ release and the interaction of PC2-IP3R-STIM1 through the PI3K/Akt signaling pathway. Inhibition of the PI3K/Akt pathway in PC1 containing cells restored intracellular Ca2+ release, increased the interaction between PC2 and IP3R and disrupted the STIM1-IP3R complex. Conversely, activation of the PI3K/Akt signaling pathway by HGF in control MDCK cells gave the reverse effects. It reduced the release of Ca2+ to levels comparable to the PC1 cells, inhibited the association PC2 and IP3R, and increased the interaction between STIM and IP3R. Overall, our studies provide a potential mechanism for the modulation of intracellular Ca2+ signaling by the polycystins. Copyright (C) 2011 S. Karger AG, Basel
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