Disease relevance of SLC38A3

• Down regulation of 3p genes, LTF, SLC38A3 and DRR1, upon growth of human chromosome 3-mouse fibrosarcoma hybrids in severe combined immunodeficiency mice [1].
• Flow cytometry and immunohistochemical analyses of the human gastric adenocarcinoma cell line MKN45G identified an intracellular peptide recognized by an anti-gastrin-17 (G17) antiserum but not by an anti-cholecystokinin-specific antiserum [2].
• In serum from patients with Zollinger-Ellison syndrome the only form of gastrin revealed by L6 was compatible with G17, and there was good agreement between estimated G17 concentrations in serum analyzed by gel filtration and by direct radioimmunoassay using L6 [3].
• SN1 shows an extremely high specificity for T ALL [4].
• We examined the effect of synthetic human gastrin-17 (G-17) on signal-transduction pathways and cell growth using 4 different human colon cancer cell lines (LoVo, COLO 320, HT-29, and HCT116) [5].

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

• The amino acid transporter SN1 with substrate specificity identical to the amino acid transport system N is expressed mainly in astrocytes and hepatocytes where it accomplishes Na(+)-coupled glutamine uptake and efflux [14].
• G-17 stimulated the production of cyclic AMP in LoVo, COLO 320, and HCT116 cells, while G-17 stimulated phosphatidylinositol hydrolysis and mobilization of intracellular calcium in HT-29 cells [5].
• Competitive binding experiments showed that the epitopes on TALLA recognized by SN1, SN1a, and SN1b are sufficiently close to one another to allow complete reciprocal inhibition of antibody binding [4].
• No significant antigenic modulation of TALLA was observed when T ALL cells were reacted with SN1 [4].
• No association between NAT1 genotype and HCC was evident overall or within the smoking stratified subgroups [15].

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

• Properties and regulation of glutamine transporter SN1 by protein kinases SGK and PKB [14].
• In contrast, the System N amino acid transporter does not co-migrate with ankyrin and fodrin, nor does the anti-fodrin antibody immunoprecipitate System N activity [22].

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