ReviewSLC17: A functionally diverse family of organic anion transporters☆
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.
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