title: Polycystin-1, 2, and STIM1 interact with IP(3)R to modulate ER Ca release through the PI3K/Akt pathway.
abstract: 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.
authors.affiliation: Department of Physiology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Netty G
authors.initials: NG
authors.lastname: Santoso
authors.forename: Liudmila
authors.initials: L
authors.lastname: Cebotaru
authors.forename: William B
authors.initials: WB
authors.lastname: Guggino
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004285:Dogs; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050396:TRPP Cation Channels / Q000378:metabolism*
chemical_list: D002118:Calcium; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D050396:TRPP Cation Channels