Polycystin-1, 2, and STIM1 Interact with IP3R to Modulate ER Ca2+ Release through the PI3K/Akt Pathway

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