Polycystin-1 interacts with inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca²⁺ signaling with implications for polycystic kidney disease

The PKD1 or PKD2 genes encode polycystins (PC) 1 and 2, which are associated with polycystic kidney disease. Previously we demonstrated that PC2 interacts with the inositol 1,4,5- trisphosphate receptor (IP₃R) to modulate Ca²⁺ signaling. Here, we investigate whether PC1 also regulates IP₃R. We generated a fragment encoding the last six transmembrane (TM) domains of PC1 and the C-terminal tail (QIF38), a section with the highest homology to PC2. Using a Xenopus oocyte Ca²⁺ imaging system, we observed that expression of QIF38 significantly reduced the initial amplitude of IP3-induced Ca²⁺ transients, whereas a mutation lacking the C-terminal tail did not. Thus, the C terminus is essential to QIF38 function. Co-immunoprecipitation assays demonstrated that through its C terminus, QIF38 associates with the IP₃-binding domain of IP₃R. A shorter PC1 fragment spanning only the last TM and the C-terminal tail also reduced IP₃-induced Ca²⁺ release, whereas another C-terminal fragment lacking any TM domain did not. Thus, only endoplasmic reticulum-localized PC1 can modulate IP₃R. Finally, we show that in the polarized Madin-Darby canine kidney cells, heterologous expression of full-length PC1 resulted in a smaller IP₃-induced Ca²⁺ response. Overexpression of the IP₃-binding domain of IP₃R reversed the inhibitory effect of PC1, suggesting interaction of full-length PC1 (or its cleavage forms) with endogenous IP₃R in Madin-Darby canine kidney cells. These results indicate that the behavior of full-length PC1 in mammalian cells is congruent with that of PC1 C-terminal fragments in the oocyte system. These data demonstrate that PC1 inhibits Ca²⁺ release, perhaps opposing the effect of PC2, which facilitates Ca²⁺ release through the IP₃R.