The molecular mechanism of SLC34 proteins: insights from two decades of transport assays and structure-function studies

  • Ian C. ForsterEmail author
Invited Review


The expression cloning some 25 years ago of the first member of SLC34 solute carrier family, the renal sodium-coupled inorganic phosphate cotransporter (NaPi-IIa) from rat and human tissue, heralded a new era of research into renal phosphate handling by focussing on the carrier proteins that mediate phosphate transport. The cloning of NaPi-IIa was followed by that of the intestinal NaPi-IIb and renal NaPi-IIc isoforms. These three proteins constitute the main secondary-active Na+-driven pathways for apical entry of inorganic phosphate (Pi) across renal and intestinal epithelial, as well as other epithelial-like organs. The key role these proteins play in mammalian Pi homeostasis was revealed in the intervening decades by numerous in vitro and animal studies, including the development of knockout animals for each gene and the detection of naturally occurring mutations that can lead to Pi-handling dysfunction in humans. In addition to characterising their physiological regulation, research has also focused on understanding the underlying transport mechanism and identifying structure-function relationships. Over the past two decades, this research effort has used real-time electrophysiological and fluorometric assays together with novel computational biology strategies to develop a detailed, but still incomplete, understanding of the transport mechanism of SLC34 proteins at the molecular level. This review will focus on how our present understanding of their molecular mechanism has evolved in this period by highlighting the key experimental findings.


Phosphate cotransport Electrophysiology Fluorometry Kinetics Structure-function 



The author wishes to acknowledge the numerous contributions made by those working in the phosphate transport field past and present. The support and encouragement given by Heini Murer and Jürg Biber (University of Zurich), Ernest Wright and his past and present colleagues Don Loo, Bruce Hirayama and Sepehr Eskandari (UCLA) and more recently the collaborations with Cristina Fenollar-Ferrer and Lucy Forrest (NIH) are particularly appreciated. Special thanks are due to colleagues, postdocs and doctoral candidates at the Murer laboratory, without whom the insights gained over the years would have been impossible, and whose names and contributions appear in the original references. Most of the studies reported here were supported by grants from the Swiss National Science Foundation and Hartmann Müller-Stiftung (University of Zurich) to the author and Heini Murer, as well as other funding sources cited in the original publications. Finally, the author acknowledges the outstanding support from Steven Petrou and colleagues at the Ion Channels in Human Diseases Laboratory (Florey Institute).


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© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Ion Channels and Human Diseases LaboratoryFlorey Institute of Neuroscience and Mental HealthParkvilleAustralia

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