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SLC38A3  -  solute carrier family 38, member 3

Homo sapiens

Synonyms: G17, N-system amino acid transporter 1, NAT1, Na(+)-coupled neutral amino acid transporter 3, SN1, ...
 
 
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Disease relevance of SLC38A3

 

High impact information on SLC38A3

  • Using intracellular pH measurements, we have now identified an orphan protein related to a vesicular neurotransmitter transporter as system N. Functional analysis shows that this protein (SN1) involves H+ exchange as well as Na+ cotransport and, under physiological conditions, mediates glutamine efflux as well as uptake [6].
  • Together with the pattern of SN1 expression, these unusual properties suggest novel physiological roles for system N in nitrogen metabolism and synaptic transmission [6].
  • The single-strand damage processed by AlkB was primarily cytotoxic and not mutagenic and was induced by SN2 methylating agents, MMS, DMS, and MeI but not by SN1 agent N-methyl-N-nitrosourea or by gamma irradiation [7].
  • At low doses of either exogenous pentagastrin or gastrin-17 (G17), cirrhotics with portacaval shunt secreted significantly greater amounts of gastric acid than unshunted subjects [8].
  • G17 and carboxyl terminal octapeptide of cholecystokinin (26-33) were equipotent in displacing tracer binding and in stimulating parietal cell function ( [14C]aminopyrine accumulation), whereas the tetrapeptide of gastrin (14-17) had a much lower potency [9].
 

Chemical compound and disease context of SLC38A3

  • In acidosis, the mRNA of kidney system N amino acid transporter SNAT3 (SLC38A3/SN1) showed a strong induction similar to that of PEPCK, whereas all other tested mRNAs encoding glutamine or glutamate transporters were unchanged or reduced in abundance [10].
  • SN1 had a hexagonal head and a long flexible tail resembling most closely the phages in Bradley's group B. The nucleic acid was found to be deoxyribonucleic acid and contained an unusual base which substituted for 35% of the guanine [11].
  • Cimetidine administration was associated with further increases in G-17, G-34, and total gastrin in normal subjects and gastric ulcer patients after meals [12].
  • Hb Madrid, in which the alanine residue at beta115 (G17) is replaced by proline, results in a moderately severe hemolytic anemia due to the disruption of an alpha helical region and the weakening of an alpha1 beta1 contact (1,2) [13].
 

Biological context of SLC38A3

 

Anatomical context of SLC38A3

  • We have cloned the human Na(+)- and H(+)-coupled amino acid transport system N (hSN1) from HepG2 liver cells and investigated its functional characteristics [16].
  • When expressed in Xenopus laevis oocytes, the transport of glutamine or asparagine via human SN1 was associated with inward currents under voltage-clamped conditions [16].
  • The MKN45G cell line had elevated in vitro growth in serum-free medium in which the proliferation of MKN45G cells but not MKN45 cells was reduced to 58% of the control value by treatment with a rabbit anti-G17 antiserum [2].
  • These immunotoxins were prepared by conjugating ricin A chain (RIA) with our recently generated murine monoclonal antibodies, SN1 and SN2, the latter of which was obtained from a hybridoma clone N6/D11 described previously by Negoro and Seon (Cancer Res., 42: 4259-4262, 1982), directed to two unique human T-cell leukemia antigens [17].
  • Human umbilical vascular endothelial cells (HUVEC) were assessed for tubule formation in the presence of amidated gastrin-17 (G17) and glycine-extended gastrin-17 (GlyG17) peptides [18].
 

Associations of SLC38A3 with chemical compounds

  • When expressed in mammalian cells, the transport function of human SN1 could be demonstrated with glutamine as the substrate in the presence of LiCl (instead of NaCl) and cysteine [16].
  • Synthetic human gastrin-17-I (G17) with a leucine substitution in the 15th position ( [Leu15]-G17) was iodinated by chloramine T; high saturable binding was found to enzyme-dispersed canine fundic mucosal cells [9].
  • [(3)H]-thymidine and bromodeoxyuridine (BrdU) incorporation determined proliferation in response to G17 in biopsy specimens incubated ex vivo [19].
  • It is proposed that the increase in cis-adduct formation due to salt results from SN1 attack of chloride ion on the BPDE carbocation, forming a trans chlorohydrin, followed by SN2 attack of DNA [20].
  • The antibodies raised neutralized both carboxy-amidated and glycine-extended G17 [21].
 

Regulatory relationships of SLC38A3

  • Coexpression of Nedd4-2 downregulated SN1-mediated transport, an effect reversed by coexpression of S422DSGK1, SGK3, and T308D,S473DPKB [14].
 

Other interactions of SLC38A3

 

Analytical, diagnostic and therapeutic context of SLC38A3

  • At each measured serum gastrin concentration after either exogenous G17 or intragastric peptone meals, cirrhotics with portacaval shunt secreted more acid than the unshunted control groups and their dose-response curve was significantly shifted to the left [8].
  • Gel filtration indicated a single peak of N-terminal immunoreactivity in plasma during infusion of 1-13 G-17 [23].
  • On high-pressure liquid chromatography the variant was resolved into a major component, which had a retention time less than 1-13 G-17, and two minor components [23].
  • The metabolism and action on basal and gastrin 17 (G-17)-stimulated acid secretion of the N-terminal 1-13 sequence of G-17 was studied in human volunteers [23].
  • 5. Its retention time during reverse phase HPLC on a C18 column also differed from those of G17 and G34 [24].

References

  1. Down regulation of 3p genes, LTF, SLC38A3 and DRR1, upon growth of human chromosome 3-mouse fibrosarcoma hybrids in severe combined immunodeficiency mice. Kholodnyuk, I.D., Kozireva, S., Kost-Alimova, M., Kashuba, V., Klein, G., Imreh, S. Int. J. Cancer (2006) [Pubmed]
  2. Intracellular gastrin in human gastrointestinal tumor cells. Watson, S.A., Durrant, L.G., Wencyk, P.M., Watson, A.L., Morris, D.L. J. Natl. Cancer Inst. (1991) [Pubmed]
  3. Heptadecapeptide gastrin: measurement in blood by specific radioimmunoassay. Dockray, G.J., Taylor, I.L. Gastroenterology (1976) [Pubmed]
  4. Molecular nature of a cell membrane antigen specific for human T-cell acute lymphoblastic leukemia. Matsuzaki, H., Seon, B.K. Cancer Res. (1987) [Pubmed]
  5. Effects of gastrin on 3',5'-cyclic adenosine monophosphate, intracellular calcium, and phosphatidylinositol hydrolysis in human colon cancer cells. Ishizuka, J., Townsend, C.M., Bold, R.J., Martinez, J., Rodriguez, M., Thompson, J.C. Cancer Res. (1994) [Pubmed]
  6. Molecular analysis of system N suggests novel physiological roles in nitrogen metabolism and synaptic transmission. Chaudhry, F.A., Reimer, R.J., Krizaj, D., Barber, D., Storm-Mathisen, J., Copenhagen, D.R., Edwards, R.H. Cell (1999) [Pubmed]
  7. Defective processing of methylated single-stranded DNA by E. coli AlkB mutants. Dinglay, S., Trewick, S.C., Lindahl, T., Sedgwick, B. Genes Dev. (2000) [Pubmed]
  8. Increased sensitivity of gastric acid secretion to gastrin in cirrhotic patients with portacaval shunt. Lenz, H.J., Struck, T., Greten, H., Koss, M.A., Eysselein, V.E., Walsh, J.H., Isenberg, J.I. J. Clin. Invest. (1987) [Pubmed]
  9. Gastrin receptors on isolated canine parietal cells. Soll, A.H., Amirian, D.A., Thomas, L.P., Reedy, T.J., Elashoff, J.D. J. Clin. Invest. (1984) [Pubmed]
  10. Regulation of renal amino acid transporters during metabolic acidosis. Moret, C., Dave, M.H., Schulz, N., Jiang, J.X., Verrey, F., Wagner, C.A. Am. J. Physiol. Renal Physiol. (2007) [Pubmed]
  11. Isolation and characterization of a bacteriophage specific for Sphaerotilus natans which contain an unusual base in its deoxyribonucleic acid. Winston, V., Thompson, T.L. Appl. Environ. Microbiol. (1979) [Pubmed]
  12. Postprandial changes in serum concentrations of gastrin-17, gastrin-34, and total gastrin in patients with duodenal or gastric ulcers and in normal subjects. Walker, K., Pinchbeck, B., Mahachai, V., Simpson, I., Kirdeikis, P., Zuk, L., Brunet, K., Sherbaniuk, R., Chitnuyanondh, L., Cherry, R. Clinical therapeutics. (1985) [Pubmed]
  13. Hb Madrid [beta115(G17)Ala-->Pro] in a Korean family with chronic hemolytic anemia. Kim, J.Y., Park, S.S., Jung, H.L., Keum, D.H., Park, H., Chang, Y.H., Lee, Y.J., Cho, H.I. Hemoglobin (2000) [Pubmed]
  14. Properties and regulation of glutamine transporter SN1 by protein kinases SGK and PKB. Boehmer, C., Okur, F., Setiawan, I., Bröer, S., Lang, F. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  15. Role of N-acetyltransferase polymorphisms in hepatitis B related hepatocellular carcinoma: impact of smoking on risk. Yu, M.W., Pai, C.I., Yang, S.Y., Hsiao, T.J., Chang, H.C., Lin, S.M., Liaw, Y.F., Chen, P.J., Chen, C.J. Gut (2000) [Pubmed]
  16. Primary structure, genomic organization, and functional and electrogenic characteristics of human system N 1, a Na+- and H+-coupled glutamine transporter. Fei, Y.J., Sugawara, M., Nakanishi, T., Huang, W., Wang, H., Prasad, P.D., Leibach, F.H., Ganapathy, V. J. Biol. Chem. (2000) [Pubmed]
  17. Specific killing of human T-leukemia cells by immunotoxins prepared with ricin A chain and monoclonal anti-human T-cell leukemia antibodies. Seon, B.K. Cancer Res. (1984) [Pubmed]
  18. Gastrin enhances the angiogenic potential of endothelial cells via modulation of heparin-binding epidermal-like growth factor. Clarke, P.A., Dickson, J.H., Harris, J.C., Grabowska, A., Watson, S.A. Cancer Res. (2006) [Pubmed]
  19. Gastrin induces proliferation in Barrett's metaplasia through activation of the CCK2 receptor. Haigh, C.R., Attwood, S.E., Thompson, D.G., Jankowski, J.A., Kirton, C.M., Pritchard, D.M., Varro, A., Dimaline, R. Gastroenterology (2003) [Pubmed]
  20. Chloride ions catalyze the formation of cis adducts in the binding of anti-benzo[a]pyrene diol epoxide to nucleic acids. Wolfe, A.R., Yamamoto, J., Meehan, T. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  21. Gastrimmune raises antibodies that neutralize amidated and glycine-extended gastrin-17 and inhibit the growth of colon cancer. Watson, S.A., Michaeli, D., Grimes, S., Morris, T.M., Robinson, G., Varro, A., Justin, T.A., Hardcastle, J.D. Cancer Res. (1996) [Pubmed]
  22. Association of hepatic system A amino acid transporter with the membrane-cytoskeletal proteins ankyrin and fodrin. Handlogten, M.E., Dudenhausen, E.E., Yang, W., Kilberg, M.S. Biochim. Biophys. Acta (1996) [Pubmed]
  23. Metabolism of the 1-13 sequence of gastrin 17 in humans and failure to influence acid secretion. Pauwels, S., Dockray, G.J., Walker, R., Marcus, S. Gastroenterology (1985) [Pubmed]
  24. Ulcerogenic tumor syndrome of the pancreas associated with a nongastrin acid secretagogue. Chey, W.Y., Chang, T.M., Lee, K.Y., Sun, G., Kim, C.K., You, C.H., Hamilton, D.L., Shah, A., Rhee, J.C., Mutt, V. Ann. Surg. (1989) [Pubmed]
 
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