Alternative titles; symbols
HGNC Approved Gene Symbol: SLC5A12
Cytogenetic location: 11p14.2 Genomic coordinates (GRCh38): 11:26,667,020-26,723,389 (from NCBI)
Normal blood lactate is maintained at about 1.5 mM, and little filtered lactate is excreted in urine. Reabsorption of lactate is mediated by the low-affinity Na(+)-coupled lactate transporter SLC5A12 in the initial part of the proximal tubule and by the high-affinity Na(+)-coupled lactate transporter SLC5A8 (608044) in the distal proximal tubule (Gopal et al., 2007).
Srinivas et al. (2005) cloned mouse Slc5a12, which they called Smct2, from a kidney cDNA library. The deduced 619-amino acid protein has 13 putative transmembrane domains, an exoplasmic N terminus, a cytoplasmic C terminus, 2 putative N-glycosylation sites, and several putative phosphorylation sites. Northern blot analysis detected 2 Slc5a12 variants in kidney and small intestine. RT-PCR also detected Slc5a12 expression in skeletal muscle. In situ hybridization showed predominant Slc5a12 expression in the early portions of mouse kidney proximal tubules and in the proximal portion of the intestinal tract.
By searching databases using mouse Slc5a12 as query, followed by RT-PCR of kidney total RNA, Gopal et al. (2007) cloned human SLC5A12. The deduced 618-amino acid protein shares 85% identity with mouse Slc5a12. In situ hybridization revealed that Slc5a12 and Slc5a8 were expressed in the apical membrane of mouse proximal tubule cells.
Srinivas et al. (2005) found that heterologous expression of mouse Slc5a12 in human cells induced Na(+)-dependent transport of lactate and nicotinate. Several other short-chain monocarboxylates competed with nicotinate for transport. Expression of Slc5a12 in Xenopus oocytes induced electrogenic and Na(+)-dependent transport of lactate, nicotinate, propionate, and butyrate.
Gopal et al. (2007) showed that human SMCT2 mediated Na(+)-coupled transport of lactate, pyruvate, and nicotinate following expression in mammalian cells or Xenopus oocytes. SMCT2 exhibited lower affinities for these substrates than those reported for SMCT1 (SLC5A8). Several nonsteroidal antiinflammatory drugs (NSAIDs) inhibited SMCT2-mediated nicotinate transport, suggesting that NSAIDs interact with this transporter.
Thangaraju et al. (2006) found that the renal expression of Slc5a8 and Slc5a12 was reduced in Cebpd (116898) +/- mice and was almost completely ablated in Cebpd -/- mice. Expression of other renal transporters, including the uric acid transporter Urat1 (SLC22A12; 607096), remained normal in Cebpd -/- mice, and expression of Slc5a8 and Slc5a12 in brain and intestine was unaffected by Cebpd deletion. Reporter gene assays using the promoter regions of human SLC5A8 and SLC5A12 confirmed that CEBPD induced expression of these transporters. Ablation of Slc5a8 and Slc5a12 in Cebpd -/- mouse kidney was accompanied by a marked increase in urinary excretion of lactate, as well as reduced blood levels of lactate. In addition, urinary excretion of urate was significantly elevated in Cebpd -/- mice, even though expression of Urat1 was not altered. Thangaraju et al. (2006) hypothesized that lactate reabsorption by SLC5A8 and SLC5A12 is coupled to urate reabsorption by URAT1 at the proximal tubule apical membrane.
Gopal et al. (2007) determined that the SLC5A12 gene contains 15 exons and spans about 50 kb.
By genomic sequence analysis, Gopal et al. (2007) mapped the SLC5A12 gene to chromosome 11p14.2.
Gopal, E., Umapathy, N. S., Martin, P. M., Ananth, S., Gnana-Prakasam, J. P., Becker, H., Wagner, C. A., Ganapathy, V., Prasad, P. D. Cloning and functional characterization of human SMCT2 (SLC5A12) and expression pattern of the transporter in kidney. Biochim. Biophys. Acta 1768: 2690-2697, 2007. [PubMed: 17692818] [Full Text: https://doi.org/10.1016/j.bbamem.2007.06.031]
Srinivas, S. R., Gopal, E., Zhuang, L., Itagaki, S., Martin, P. M., Fei, Y.-J., Ganapathy, V., Prasad, P. D. Cloning and functional identification of slc5a12 as a sodium-coupled low-affinity transporter for monocarboxylates (SMCT2). Biochem. J. 392: 655-664, 2005. [PubMed: 16104846] [Full Text: https://doi.org/10.1042/BJ20050927]
Thangaraju, M., Ananth, S., Martin, P. M., Roon, P., Smith, S. B., Sterneck, E., Prasad, P. D., Ganapathy, V. c/ebp-delta null mouse as a model for the double knock-out of slc5a8 and slc5a12 in kidney. J. Biol. Chem. 281: 26769-26773, 2006. [PubMed: 16873376] [Full Text: https://doi.org/10.1074/jbc.C600189200]