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

Cellular Physiology and Biochemistry

关键词: Polycystic Kidney Disease (ADPKD);    Cyst;    Calcium;    PI3K/Akt;    Polycystin-1;    Polycystin-2;    IP3R;    STIM1;   

DOI  :  10.1159/000330080

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

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.

【 授权许可】

CC BY-NC-ND