Extracellular Phosphate as a Signaling Molecule

Phosphorus is involved in various biological processes including membrane integrity, maintenance and inheritance of genetic materials, energy metabolism, intracellular signaling and skeletal mineralization. In addition, accumulating evidences have indicated that alteration in the levels of extracellular inorganic phosphate (Pi) itself triggers signaling to regulate gene expression and cellular functions in some cell types. In bone cells such as osteoblasts and chondrocytes, extracellular Pi modulates cell proliferation, differentiation, mineralization and apoptosis. In extraskeletal tissues, extracellular Pi also exerts various effects. For example, increased extracellular Pi results in the calcification associated with the upregulation of osteoblast marker genes in vascular smooth muscle cells. As to the mechanistic aspects, it is suggested that an increase in extracellular Pi triggers signal transduction via the PiT1 type III sodium/phosphate (Na(+)/Pi) cotransporter and ERK1/2 pathway. Unicellular organisms such as bacteria and yeast sense the environmental Pi with a protein complex located in the plasma membrane, which regulates the expression of multiple genes involved in Pi uptake and metabolism to adapt to its availability. In mammals that are multicellular organisms, Pi availability should be sensed both at a cellular level to regulate the function of each cell and as a whole body to maintain the Pi homeostasis of the extracellular fluid. Although the responsiveness to the increased extracellular Pi suggests the existence of Pi-sensing mechanism in mammalian cells as well, it is unknown whether the sensing of Pi availability at a cellular level and that at a whole-body level share the same pathway or not. This chapter will review the findings regarding the regulation of various cellular functions by extracellular Pi, and also discuss the current concept on the mechanism for Pi-sensing.