Complex phosphate sensing system regulating phosphate homeostasis

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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