The Orphan Transporter Rxt1/NTT4 (SLC6A17) Functions as a Synaptic Vesicle Amino Acid Transporter Selective for Proline, Glycine, Leucine, and Alanine
Abstract
Rxt1/NTT4 (SLC6A17) belongs to a gene family of "orphan transporters" whose substrates and consequently functions remain unidentified. Although Rxt1/NTT4 was previously thought to function as a sodium-dependent plasma membrane transporter, recent studies localized the protein to synaptic vesicles of glutamatergic and GABAergic neurons. Here, we provide evidence indicating that Rxt1/NTT4 functions as a vesicular transporter selective for proline, glycine, leucine, and alanine. Using Western blot, immunoprecipitation, immunocytochemistry, and polymerase chain reaction approaches, we demonstrate that PC12 cells express the Rxt1/NTT4 gene and protein. Small interfering RNA (siRNA)-mediated knockdown of Rxt1/NTT4 in PC12 cells resulted in selective reductions in uptake levels for proline, glycine, leucine, and alanine. Likewise, gas chromatography analysis of amino acid content in an enriched synaptic vesicle fraction from wild-type and siRNA-Rxt1/NTT4 PC12 cells revealed that proline, glycine, leucine, and alanine levels were decreased in siRNA-treated cells compared with wild-type cells. Furthermore, Rxt1/NTT4-transfected Chinese hamster ovary (CHO) cells exhibited significant uptake increases of these amino acids compared with mock-transfected CHO cells. Finally, proline uptake in both PC12 cells and Rxt1/NTT4-transfected CHO cells was dependent on the electrochemical gradient maintained by the vacuolar-type H(+)-ATPase. These data indicate that the orphan Rxt1/NTT4 protein fun…
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Both human and mouse β-cells express Slc6a17/SLC6a17, which encodes a synaptic vesicle glycine transporter.
“Both human and mouse β-cells also express Slc6a17/SLC6a17 (3, 68, 146, 475) that encodes a synaptic vesicle glycine transporter (502).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [502]
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NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders
Lau, C. G., & Zukin, R. S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2153 · Cited by 1,159 · cited 1× · see citing works
“Heteromeric NMDA receptors are ubiquitously distributed throughout the brain, participating in a variety of functions, including neuronal development, synaptic plasticity, learning, and memory (Scheetz and Constantine-Paton, 1994; Kato et al., 1999; Albensi, 2007; Lau and Zukin, 2007).”
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Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
SLC6 Transporter Folding Diseases and Pharmacochaperoning
Freissmuth, M., Stockner, T., & Sucic, S. (2017) · Handbook of experimental pharmacology · doi:10.1007/164_2017_71 · Cited by 42 · see citing works
- Authors
- Parra, L. A., Baust, T., El Mestikawy, S., Quiroz, M., Hoffman, B., Haflett, J. M., Yao, J. K., & Torres, G. E.
- Affiliations
- University of Pittsburgh (US)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2008-12
- Volume
- 74
- Issue
- 6
- Pages
- 1521-1532
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W2141090437
- Cited by
- 53
- References
- 1
- Citations by year
- 2025: 7 · 2024: 2 · 2023: 4 · 2022: 1 · 2021: 2 · 2020: 5 · 2019: 2 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 2 · 2014: 2 · 2013: 5 · 2012: 4
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- orphan transporter, synaptic vesicles, amino acid transporters, proline uptake, glycine, leucine, alanine, vesicle trafficking, vacuolar H+-ATPase, synaptic transmission, glutamatergic neurons, GABAergic neurons, PC12 cells
- MeSH terms
- Alanine, Amino Acids, Animals, Cricetulus, Glycine, Cricetinae, Humans, Leucine, Nerve Tissue Proteins, Proline, Synaptic Vesicles, CHO Cells, PC12 Cells, Membrane Transport Proteins, Amino Acid Transport Systems, RNA, Small Interfering, Mice, Rats, In Vitro Techniques
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