Dysregulation of Ca(2+) 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 Ca(2+) signaling. Expression of full-length PC1 in MDCK cells inhibited intracellular Ca(2+) release in response to ATP when compared to control cells. This phenotype correlated with reduced interaction of endogenous PC2 and IP(3)R in PC1-containing cells. We also found that endogenous STIM1 also interacted with the IP(3)R, and this interaction was enhanced by PC1 expression. Increased interaction between STIM1 and IP(3)R inhibited Ca(2+) release. PC1 regulates intracellular Ca(2+) release and the interaction of PC2-IP(3)R-STIM1 through the PI3K/Akt signaling pathway. Inhibition of the PI3K/Akt pathway in PC1 containing cells restored intracellular Ca(2+) release, increased the interaction between PC2 and IP(3)R and disrupted the STIM1-IP(3)R complex. Conversely, activation of the PI3K/Akt signaling pathway by HGF in control MDCK cells gave the reverse effects. It reduced the release of Ca(2+) to levels comparable to the PC1 cells, inhibited the association PC2 and IP(3)R, and increased the interaction between STIM and IP(3)R. Overall, our studies provide a potential mechanism for the modulation of intracellular Ca(2+) signaling by the polycystins.
Copyright © 2011 S. Karger AG, Basel.