In vertebrates, the level of inorganic phosphate (Pi) is tightly balanced both inside the cell and in the whole organism. A number of different Na+-dependent Pi cotransport systems involved in Pi homeostasis have been identified and characterized at the molecular level in the past 7 years. The transporters constitute three different protein families denoted NaPi-I, NaPi-II and NaPi-III. NaPi-I from the rabbit was the first member of this family to be cloned. However, it still resists efforts to unravel its physiological role and a clear-cut functional identity: is it a Cl-channel, a Na+/Pi cotransporter, a regulator, or does it perform a combination of these functions? These questions provide a slight taste of the problems associated with orphan genes derived from sequencing projects. The members of the NaPi-II protein family are crucially involved in tightly controlled renal Pi excretion and, as recently discovered, intestinal Pi absorption. The expression and the cellular distribution of NaPi-II in the proximal tubular epithelium are affected by hormonal and metabolic factors known to influence extracellular fluid Pi homeostasis. Recently, the expression of NaPi-II has been demonstrated in osteoclasts and brain;however, the physiological roles of NaPi-II in these tissues remain to be established. The members of the third protein family, NaPi-III, have been identified on the basis of their function as viral receptors. The widespread expression of this family suggests that NaPi-III is involved in supplying the basic cellular metabolic needs for Pi.

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