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Complex phosphate sensing system regulating phosphate homeostasis

调节磷酸盐稳态的复杂磷酸盐传感系统

基本信息

批准号：
13470013
负责人：
TAKEDA Eiji
金额：
$ 9.28万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

Inorganic phosphate (Pi) is required for cellular function and skeletal mineralization. Serum Pi level is maintained within a narrow range through a complex interplay between intestinal absorption, exchange with intracellular and bone storage pools, and renal tubular reabsorption. Pi is abundant in the diet, and intestinal absorption of Pi is efficient and minimally regulated. In a survey in the United States and in Japan, the amount of phosphorus from food is gradually increasing. It is thought that excess amounts of phosphorus intake for long periods are a strong factor in bone impairment and ageing. The restriction of phosphorus intake seems to be important under low calcium intake to keep QOL on high levelThe kidney is a major regulator of Pi homeostasis and can increase or decrease its Pi reabsorptive capacity to accommodate Pi need. The crucial regulated step in Pi homeostasis is the transport of Pi across the renal proximal tubule. Type II sodium-dependent phosphate (Na/Pi) cotr … More ansporter (NPT2) is the major molecule in the renal proximal tubule and is regulated by hormones and nonhormonal factors. Recent studies of inherited and acquired hypophosphatemia which exhibit similar biochemical and clinical features, have led to the identification of novel genes, PHEX and FGF23, that play a role in the regulation of Pi homeostasis. The PHEX gene encodes an endopeptidase, predominantly expressed in bone and teeth but not in kidney. FGF-23 may be a substrate of this endopeptidase and inhibit renal Pi reabsorptionCaveolae-like microdomains (CM) are thought to play an important role in the apical targeting and translocational regulation of NPT2 in response to parathyroid hormone (PTH). NPT2 was primarily localized in CM derived from the apical plasma membrane of OK N2 cells. PTH reduced the levels of immunoreactive NPT2 in CM ; this effect was blocked by methyl-3-cyclodextrin, an inhibitor of CM, and cytochalasin D, which depolymerizes actin. PTH activated both PKA and PKCa in CM, and increased the phosphorylation of 80 kDa and 250 kDa substrates ; we identified ezrin as a candidate protein for the 80 kDa substrateOur results suggest that NPT2 is localized to plasma membrane CM and that these CM not only play a role in PTH-and actin-mediated regulation of NPT2 surface expression, but also in the compartmentalization of PTH-responsive signaling molecules. Thus, CM appear to be important microdomains involving phosphate sensing system regulating phosphate homeostasis Less

无机磷酸盐（Pi）是细胞功能和骨骼矿化所必需的。血清Pi水平通过肠道吸收、与细胞内和骨储存池交换以及肾小管重吸收之间的复杂相互作用维持在一个狭窄的范围内。日粮中含有丰富的π，其肠道吸收效率高，且受调控最小。在美国和日本进行的一项调查显示，食物中的磷含量正在逐渐增加。人们认为，长期摄入过量的磷是骨骼损伤和衰老的一个重要因素。在低钙摄入的情况下，限制磷的摄入对维持高水平的生活质量很重要。肾脏是磷稳态的主要调节者，可以增加或减少其磷的再吸收能力以适应磷的需要。Pi稳态的关键调控步骤是Pi通过肾近端小管的运输。II型钠依赖性磷酸盐（Na/Pi）转运蛋白（NPT2）是肾近端小管中的主要分子，受激素和非激素因素的调节。最近对表现出相似生化和临床特征的遗传性和获得性低磷血症的研究发现了在Pi稳态调节中起作用的新基因PHEX和FGF23。PHEX基因编码一种内肽酶，主要在骨骼和牙齿中表达，但在肾脏中不表达。FGF-23可能是这种内多肽酶的底物，并抑制肾Pi的再吸收。小窝样微结构域（CM）被认为在响应甲状旁腺激素（PTH）的NPT2的根尖靶向和易位调节中起重要作用。NPT2主要定位于来自于OK N2细胞顶质膜的CM中。甲状旁腺素降低CM中免疫反应性NPT2的水平；这种作用被甲基-3-环糊精（一种CM抑制剂）和细胞松弛素D（能解聚肌动蛋白）阻断。PTH激活CM中的PKA和PKCa，增加80 kDa和250 kDa底物的磷酸化；我们发现ezrin是80 kDa亚基的候选蛋白。我们的研究结果表明，NPT2定位于质膜CM，这些CM不仅在pth和肌动蛋白介导的NPT2表面表达调控中起作用，而且在pth响应信号分子的区隔化中起作用。因此，CM似乎是参与磷酸盐传感系统调节磷酸盐稳态的重要微结构域