Alternative titles; symbols
HGNC Approved Gene Symbol: SLC17A6
Cytogenetic location: 11p14.3 Genomic coordinates (GRCh38): 11:22,338,381-22,379,503 (from NCBI)
Aihara et al. (2000) isolated a partial sequence of rat Slc17a6, which they designated Dnpi, that was upregulated during differentiation in a rat pancreatic acinar cell line. They used this sequence to clone full-length human SLC17A6 from a thalamus cDNA library. The deduced 582-amino acid protein has a calculated molecular mass of about 64.4 kD. SLC17A6 contains 8 putative transmembrane segments. SLC17A6 shares 82% sequence identity with SLC17A7 (605208), which the authors called BNPI, and 48% identity with EAT4, a sodium-inorganic phosphate cotransporter of C. elegans. Northern blot analysis detected SLC17A6 transcripts of 4.1 and 4.4 kb expressed predominantly in adult and fetal brain. Analysis of specific brain regions indicated highest expression in medulla, substantia nigra, subthalamic nucleus, and thalamus, with low levels in cerebellum and hippocampus. Aihara et al. (2000) found that, in these regions, the expression pattern of SLC17A6 was the reverse of that shown for SLC17A7.
Bai et al. (2001) cloned mouse Slc17a6, which they designated Vglut2. Mouse Slc17a6 contains 582 amino acids and shares 97% sequence identity with human SLC17A6. Northern blot analysis of mouse tissues detected expression of a 3.8-kb transcript only in brain. In situ hybridization of mouse brain slices showed expression in neuron-rich regions of the cerebral cortex, hippocampus, hypothalamus, and thalamus.
Aihara et al. (2000) demonstrated Na(+)-dependent uptake of radiolabeled inorganic phosphate following expression of SLC17A6 in Xenopus oocytes.
Following expression of mouse Slc17a6 in a rat pheochromocytoma cell line, Bai et al. (2001) demonstrated accumulation of radiolabeled glutamate by synaptic vesicles, but not by plasma membrane vesicles. The transport system did not recognize aspartate, and transport was blocked by an inhibitor of vesicular glutamate transport and by an anion channel blocker. Uptake was also pH dependent, with highest glutamate uptake between pH 7.0 and 7.5. Bai et al. (2001) concluded that the characteristics of glutamate transport by Slc17a6 were consistent with those of a vesicular membrane transporter. They proposed that, like SLC17A7, SLC17A6 may be a bifunctional transporter that transports phosphate at the plasma membrane and glutamate in synaptic vesicles.
Fremeau et al. (2004) showed that VGLUT1 (SLC17A7; 605208) and VGLUT2 target to distinct synaptic release sites formed by a single hippocampal neuron during development. Developmental coexpression of VGLUT2 with VGLUT1 may occur at multiple synapses.
For a discussion of a possible role of the SLC17A6 gene in nicotine dependence, see 188890.
Aihara et al. (2001) determined that the SLC17A6 gene contains 12 exons and spans about 40 kb.
By FISH, Aihara et al. (2001) mapped the SLC17A6 gene to chromosome 11p14.3.
Lagerstrom et al. (2010) stated that complete deletion of Vglut2 in mice disrupts respiration at birth. Using several genetic mouse models, Lagerstrom et al. (2010) showed that targeted deletion of Vglut2 in a subpopulation of dorsal root ganglion (DRG) neurons that partly overlapped with Trpv1 (602076)-positive primary afferents resulted in severe itch, as demonstrated by debilitating spontaneous scratching. Scratching was alleviated by antihistamine treatment or deletion of the Grp receptor (GRPR; 305670), suggesting that itch in these Vglut2 mutant mice had histamine-dependent and -independent components. These Vglut2 mutant mice also showed reduced responsiveness to thermal and inflammatory pain, but not mechanical pain.
Liu et al. (2010) deleted the Vglut2 gene specifically in mouse Nav1.8 (SCN10A; 604427)-expressing DRG neurons. These mice showed deficits in response to various painful stimuli, including mechanical, heat, capsaicin, inflammation, and neuropathic pain. Deficient pain responses were accompanied by enhanced sensitivity to both histamine-dependent and -independent itch pathways and development of spontaneous scratching and skin lesions. Intradermal capsaicin injection evoked pain responses in wildtype mice, but it promoted itch responses in mutant mice. In wildtype mice, itch caused by injection of pruritogenic compounds was masked by painful coinjection of capsaicin; however, this masking of itch by pain was not observed in Vglut2 mutant mice.
Aihara, Y., Mashima, H., Onda, H., Hisano, S., Kasuya, H., Hori, T., Yamada, S., Tomura, H., Yamada, Y., Inoue, I., Kojima, I., Takeda, J. Molecular cloning of a novel brain-type Na(+)-dependent inorganic phosphate cotransporter. J. Neurochem. 74: 2622-2625, 2000. [PubMed: 10820226] [Full Text: https://doi.org/10.1046/j.1471-4159.2000.0742622.x]
Aihara, Y., Onda, H., Teraoka, M., Yokoyama, Y., Seino, Y., Kasuya, H., Hori, T., Tomura, H., Inoue, I., Kojima, I., Takeda, J. Assignment of SLC17A6 (alias DNPI), the gene encoding brain/pancreatic islet-type Na(+)-dependent inorganic phosphate cotransporter to human chromosome 11p14.3. Cytogenet. Cell Genet. 92: 167-169, 2001. [PubMed: 11306821] [Full Text: https://doi.org/10.1159/000056893]
Bai, L., Xu, H., Collins, J. F., Ghishan, F. K. Molecular and functional analysis of a novel neuronal vesicular glutamate transporter. J. Biol. Chem. 276: 36764-36769, 2001. [PubMed: 11432869] [Full Text: https://doi.org/10.1074/jbc.M104578200]
Fremeau, R. T., Jr., Kam, K., Qureshi, T., Johnson, J., Copenhagen, D. R., Storm-Mathisen, J., Chaudhry, F. A., Nicoll, R. A., Edwards, R. H. Vesicular glutamate transporters 1 and 2 target to functionally distinct synaptic release sites. Science 304: 1815-1819, 2004. [PubMed: 15118123] [Full Text: https://doi.org/10.1126/science.1097468]
Lagerstrom, M. C., Rogoz, K., Abrahamsen, B., Persson, E., Reinius, B., Nordenankar, K., Olund, C., Smith, C., Mendez, J. A., Chen, Z.-F., Wood, J. N., Wallen-Mackenzie, A., Kullander, K. VGLUT2-dependent sensory neurons in the TRPV1 population regulate pain and itch. Neuron 68: 529-542, 2010. [PubMed: 21040852] [Full Text: https://doi.org/10.1016/j.neuron.2010.09.016]
Liu, Y., Samad, O. A., Zhang, L., Duan, B., Tong, Q., Lopes, C., Ji, R.-R., Lowell, B. B., Ma, Q. VGLUT2-dependent glutamate release from nociceptors is required to sense pain and suppress itch. Neuron 68: 543-556, 2010. [PubMed: 21040853] [Full Text: https://doi.org/10.1016/j.neuron.2010.09.008]