Review
SLC17: A functionally diverse family of organic anion transporters

https://doi.org/10.1016/j.mam.2012.05.004Get rights and content

Abstract

Molecular studies have determined that the SLC17 transporters, a family of nine proteins initially implicated in phosphate transport, mediate the transport of organic anions. While their role in phosphate transport remains uncertain, it is now clear that the transport of organic anions facilitated by this family of proteins is involved in diverse processes ranging from the vesicular storage of the neurotransmitters, to urate metabolism, to the degradation and metabolism of glycoproteins.

Section snippets

Phylogeny of the SLC17 family

The SLC17 family of transporters is a group of nine structurally related proteins (Fig. 1) that mediate the transmembrane transport of organic anions (Table 1). The first characterized members of this family, the type I phosphate transporters (SLC17A1–4), were initially identified as Na+-dependent inorganic phosphate (Pi) transporters. More recent work has, however, determined the type I phosphate transporters are involved in the transport of organic anions. Other identified mammalian members

History of identification and cloning

The first SLC17 family member to be characterized, SLC17A1, was identified through a functional screen for Na+-dependent inorganic phosphate (Pi) transporters (Murer et al., 2000). The screen led to isolation of a sequence encoding a 465 amino acid protein that was designated NaPi-1. A human orthologue of NaPi-1 and three other closely related proteins have been identified through genomic analysis, and designated NPT1 (SLC17A1/NaPi-1), NPT3 (SLC17A2), NPT4 (SLC17A3), and NPT5 (SLC17A4) (

History of identification, genetics, and cloning

The identification of free sialic acid as the material accumulated in the enlarged lysosomes of individuals with sialic acid storage disorders (Salla Disease and infantile sialic acid storage disease (ISSD)) led to the characterization of a transport system that recognizes sialic acids and several additional acidic sugars including glucuronic acid (Aula and Gahl, 2001). Genetic linkage studies of patients with Salla Disease identified a gene associated with the disease on chromosome 6q14-q15

History of identification and cloning

Glutamate is the primary excitatory neurotransmitter in the mammalian nervous system. Release of glutamate at synapses requires its transport into synaptic vesicles that fuse with the plasma membrane and release their contents during synaptic transmission. SLC17A7 encoding VGLUT1 was identified in a screen for cDNAs upregulated in cerebellar granule cells in response to subtoxic levels of the glutamate receptor agonist NMDA (Ni et al., 1994) and SLC17A6 encoding VGLUT2 was isolated in a screen

History of identification, genetics, and cloning

Studies demonstrating uptake of ATP into chromaffin granule vesicles and synaptic vesicles indicated that vesicular exocytosis is a primary mechanism for release of purines as signaling molecules. Although the vesicular nucleotide transport activity had been studied for several decades, the protein mediating this activity was only identified in 2008 when a genomic DNA database screen for sequences encoding proteins with structural similarity to other SLC17 family members identified SLC17A9 on

Transport models and structure–function studies

The SLC17 family members share a similar structure. They are predicted to have 12 transmembrane segments with the amino and carboxy termini located in the cytoplasm. The greatest divergence among the proteins occurs in the cytoplamsic termini and the first lumenal loop. Homology modeling with the glycerol phosphate transporter GlPT and site directed mutagenesis have been used to identify residues that are likely involved in transport process in VGLUT1, VGLUT2, NaPi-1, and sialin (Juge et al.,

Medical relevance

No drugs targeting SLC17 family members are currently used to treat human diseases. However, given their functions (Fig. 3), the potential for pharmacological targeting is great and the implications diverse.

The association of polymorphisms in SLC17A1/NPT1 and SLC17A3/NPT4 and their functional characterization as urate transporters suggest that manipulations that increase their expression or activity might be useful for the treatment of hyperuricemia and gout. Alternatively, their role in

Acknowledgements

The author is supported in part by funding from the NINDS and the March of Dimes Foundation.

References (46)

  • K. Miyamoto et al.

    Sodium-dependent phosphate cotransporters: lessons from gene knockout and mutation studies

    J. Pharm. Sci.

    (2011)
  • N. Pietrancosta et al.

    Rose Bengal analogs and vesicular glutamate transporters (VGLUTs)

    Bioorg. Med. Chem.

    (2010)
  • J. Ruel et al.

    Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice

    Am. J. Hum. Genet.

    (2008)
  • M.N. Sathe et al.

    Regulation of purinergic signaling in biliary epithelial cells by exocytosis of SLC17A9-dependent ATP-enriched vesicles

    J. Biol. Chem.

    (2011)
  • R.P. Seal et al.

    Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3

    Neuron

    (2008)
  • Y. Shigeri et al.

    Molecular pharmacology of glutamate transporters, EAATs and VGLUTs

    Brain Res. Brain Res. Rev.

    (2004)
  • A. Tokunaga et al.

    Involvement of SLC17A9-dependent vesicular exocytosis in the mechanism of ATP release during T cell activation

    J. Biol. Chem.

    (2010)
  • S.M. Voglmaier et al.

    Do different endocytic pathways make different synaptic vesicles?

    Curr. Opin. Neurobiol.

    (2007)
  • C.C. Wreden et al.

    Varied mechanisms underlie the free sialic acid storage disorders

    J. Biol. Chem.

    (2005)
  • Y. Aihara et al.

    Molecular cloning of a novel brain-type Na(+)-dependent inorganic phosphate cotransporter

    J. Neurochem.

    (2000)
  • B. Alberts et al.

    Molecular Biology of the Cell

    (2008)
  • J. Almqvist et al.

    Docking and homology modeling explain inhibition of the human vesicular glutamate transporters

    Protein Sci.

    (2007)
  • P. Aula et al.
  • Cited by (95)

    View all citing articles on Scopus

    Publication in part sponsored by the Swiss National Science Foundation through the National Center of Competence in Research (NCCR) TransCure, University of Bern, Switzerland; Director Matthias A. Hediger; Web: http://www.transcure.ch.

    View full text