Proximal tubular handling of phosphate: A molecular perspective

Members of the SLC34 gene family of solute carriers encode for three Na+-dependent phosphate (P-i) cotransporter proteins, two of which (NaPi-IIa/SLC34A1 and NaPi-IIc/SLC34A3) control renal reabsorption of P-i in the proximal tubule of mammals, whereas NaPi-IIb/SCLC34A2 mediates P-i transport in organs other than the kidney. The P-i transport mechanism has been extensively studied in heterologous expression systems and structure-function studies have begun to reveal the intricacies of the transport cycle at the molecular level using techniques such as cysteine scanning mutagenesis, and voltage clamp fluorometry. Moreover, sequence differences between the three types of cotransporters have been exploited to obtain information about the molecular determinants of hormonal sensitivity and electrogenicity. Renal handling of P-i is regulated by hormonal and non-hormonal factors. Changes in urinary excretion of P-i are almost invariably mirrored by changes in the apical expression of NaPi-IIa and NaPi-IIc in proximal tubules. Therefore, understanding the mechanisms that control the apical expression of NaPi-IIa and NaPi-IIc as well as their functional properties is critical to understanding how an organism achieves P-i homeostasis.