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

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.