Mechanisms of phosphate transport

Abstract

Over the past 25 years, successive cloning of SLC34A1, SLC34A2 and SLC34A3, which encode the sodium-dependent inorganic phosphate (P$_{i}$) cotransport proteins 2a-2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal P$_{i}$ transport. P$_{i}$ and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these P$_{i}$ transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial P$_{i}$ transport with effects on serum P$_{i}$ levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic P$_{i}$ homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport P$_{i}$, whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain P$_{i}$ homeostasis in patients with chronic kidney disease - a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences.