Polycystin 2 interacts with type I inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling
Polycystin 2 interacts with type I inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling
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DOI：
10.1074/jbc.m510082200
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发表时间：
2005-12-16
影响因子：
4.8
通讯作者：
Guggino, WB
中科院分区：
文献类型：
--
作者：
Li, Y;Wright, JM;Guggino, WB
常染色体显性多囊肾病是肾衰竭的常见原因，由PKD 1或PKD 2基因突变引起。PKD基因产物多囊蛋白（PC）1和2的确切功能仍有争议。PC 2已经定位于许多细胞区室，包括内质网、质膜和纤毛。目前还不清楚什么样的池是最相关的生理功能作为一个假定的钙离子通道。我们采用了非洲爪蟾卵母细胞钙离子成像系统，直接调查的作用，PC 2肌醇1，4，5-三磷酸（IP 3）依赖的Ca 2+信号。在细胞外Ca 2+不存在的情况下，在笼状IP 3的UV光解后记录胞质Ca 2+信号。我们证明，PC 2的过表达，以及I型IP 3受体（IP 3R），显着延长IP 3诱导的Ca 2+瞬变的半衰期（t（1/2））。然而，过表达疾病相关的PC 2突变体，点突变D511 V和C-末端截短突变R742 X并不改变t（1/2）。此外，我们发现D511 V过表达显著降低了IP 3诱导的Ca 2+瞬变的幅度。有趣的是，PC 2的C末端的过表达不仅显著降低了振幅，而且延长了t（1/2）。免疫共沉淀试验表明，PC 2与IP 3R通过其C末端的物理相互作用。两者合计，我们的数据表明，PC 2和IP 3R功能相互作用，调节细胞内Ca 2+信号。因此，PC 1或PC 2中的突变可能导致细胞内Ca 2+信号的失调，这反过来又可能导致常染色体显性多囊肾病的病理学。
Autosomal dominant polycystic kidney disease, a common cause of renal failure, arises from mutations in either the PKD1 or the PKD2 gene. The precise function of both PKD gene products polycystins (PCs) 1 and 2 remain controversial. PC2 has been localized to numerous cellular compartments, including the endoplasmic reticulum, plasma membrane, and cilia. It is unclear what pools are the most relevant to its physiological function as a putative Ca2+ channel. We employed a Xenopus oocyte Ca2+ imaging system to directly investigate the role of PC2 in inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ signaling. Cytosolic Ca2+ signals were recorded following UV photolysis of caged IP3 in the absence of extracellular Ca2+. We demonstrated that overexpression of PC2, as well as type I IP3 receptor (IP3R), significantly prolonged the half-decay time (t(1/2)) of IP3-induced Ca2+ transients. However, over-expressing the disease-associated PC2 mutants, the point mutation D511V, and the C-terminally truncated mutation R742X did not alter the t(1/2). In addition, we found that D511V overexpression significantly reduced the amplitude of IP3-induced Ca2+ transients. Interestingly, overexpression of the C terminus of PC2 not only significantly reduced the amplitude but also prolonged the t(1/2). Co-immunoprecipitation assays indicated that PC2 physically interacts with IP3R through its C terminus. Taken together, our data suggest that PC2 and IP3R functionally interact and modulate intracellular Ca2+ signaling. Therefore, mutations in either PC1 or PC2 could result in the misregulation of intracellular Ca2+ signaling, which in turn could contribute to the pathology of autosomal dominant polycystic kidney disease.