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Mechanisms of phosphate transport


Levi, Moshe; Gratton, Enrico; Forster, Ian C; Hernando, Nati; Wagner, Carsten A; Biber, Juerg; Sorribas, Victor; Murer, Heini (2019). Mechanisms of phosphate transport. Nature Reviews. Nephrology, 15(8):482-500.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:August 2019
Deposited On:09 Jan 2020 10:16
Last Modified:19 Feb 2020 09:19
Publisher:Nature Publishing Group
ISSN:1759-5061
OA Status:Closed
Publisher DOI:https://doi.org/10.1038/s41581-019-0159-y
PubMed ID:31168066

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