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

Yun Li, Netty G. Santoso, Shengqiang Yu, Owen M. Woodward, Feng Qian, William B. Guggino

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)36431-36441
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number52
DOIs
StatePublished - Dec 25 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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