Abstract
Inorganic phosphate (Pi) is an essential nutrient for the maintenance of cells. In healthy mammals, extracellular Pi is maintained within a narrow concentration range of 0.70 to 1.55 mM. Mammalian cells depend on Na+/Pi cotransporters for Pi absorption, which have been well studied. However, a new type of sodium-independent Pi transporter has been identified. This transporter assists in the absorption of Pi by intestinal cells and renal proximal tubule cells and in the reabsorption of Pi by osteoclasts and capillaries of the blood–brain barrier (BBB). Hyperphosphatemia is a risk factor for mineral deposition, the development of diseases such as osteoarthritis, and vascular calcifications (VCs). Na+-independent Pi transporters have been identified and biochemically characterized in vascular smooth muscle cells (VSMCs), chondrocytes, and matrix vesicles, and their involvement in mineral deposition in the extracellular microenvironment has been suggested. According to the growth rate hypothesis, cancer cells require more phosphate than healthy cells due to their rapid growth rates. Recently, it was demonstrated that breast cancer cells (MDA-MB-231) respond to high Pi concentration (2 mM) by decreasing Na+-dependent Pi transport activity concomitant with an increase in Na+-independent (H+-dependent) Pi transport. This Pi H+-dependent transport has a fundamental role in the proliferation and migratory capacity of MDA-MB-231 cells. The purpose of this review is to discuss experimental findings regarding Na+-independent inorganic phosphate transporters and summarize their roles in Pi homeostasis, cancers and other diseases, such as osteoarthritis, and in processes such as VC.
Highlights
Inorganic phosphate (Pi) is an essential nutrient for the formation of ATP skeletal mineralization and the constituents of DNA, RNA, phospholipids and a variety of phosphorylated metabolic intermediates [1,2]
We review the mechanisms of Na+-independent phosphate transporters present in some tissues and discuss their possible roles in the regulation of Pi homeostasis and the development of some diseases
It is speculated that phosphate exits across the basolateral membrane (BLM) by moving down an electrical gradient; as the cytosolic free phosphate concentration is approximately 1.0 mM and the plasma Pi concentration is 2.5–3.0 mM, the transmembrane voltage plays an essential role in BLM transport [10]
Summary
Inorganic phosphate (Pi) is an essential nutrient for the formation of ATP skeletal mineralization and the constituents of DNA, RNA, phospholipids and a variety of phosphorylated metabolic intermediates [1,2]. The SLC20 family comprises two members, i.e., PiT-1 (encoded by SLC20A1) and PiT-2 (encoded by SLC20A2), both of which are sodium–phosphate cotransporters that preferably carry monovalent inorganic phosphate (H2PO4−) together with two sodium ions. These transporters are expressed almost exclusively in the kidney [4,5]. The SLC34 family contains three members, namely NaPi-IIa (SLC34A1), NaPi-IIb (SLC34A2) and NaPi-IIc (SLC34A3), all of which are sodium–phosphate cotransporters; they vary in their biochemical kinetics These proteins transport divalent inorganic phosphate (HPO42−) together with two or three sodium ions [5,6]. We review the mechanisms of Na+-independent phosphate transporters present in some tissues and discuss their possible roles in the regulation of Pi homeostasis and the development of some diseases
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