scholarly journals System A amino acid transporters regulate glutamine uptake and attenuate antibody-mediated arthritis

Immunology ◽  
2015 ◽  
Vol 146 (4) ◽  
pp. 607-617 ◽  
Author(s):  
Bruno Raposo ◽  
Daniëlle Vaartjes ◽  
Emma Ahlqvist ◽  
Kutty-Selva Nandakumar ◽  
Rikard Holmdahl
Keyword(s):  
Amino Acid ◽  
Amino Acid Transporters ◽  
System A ◽  
Glutamine Uptake

Amino acid transporters: éminences grises of nutrient signalling mechanisms?

2009 ◽  
Vol 37 (1) ◽  
pp. 237-241 ◽  
Author(s):  
Peter M. Taylor
Keyword(s):  
Amino Acid ◽  
Binding Sites ◽  
Mammalian Target Of Rapamycin ◽  
Amino Acid Transporters ◽  
System A ◽  
System L ◽  
Underlying Mechanisms ◽  
Substrate Binding Sites ◽  
Amino Acid Concentrations ◽  
Mtor Signalling

Nutrient signalling by the mTOR (mammalian target of rapamycin) pathway involves upstream sensing of free AA (amino acid) concentrations. Several AA-regulated kinases have recently been identified as putative intracellular AA sensors. Their activity will reflect the balance between AA flows through underlying mechanisms which together determine the size of the intracellular free AA pool. For indispensable AAs, these mechanisms are primarily (i) AA transport across the cell membrane, and (ii) protein synthesis/breakdown. The System L AA transporter is the primary conduit for cellular entry of indispensable neutral AAs (including leucine and phenylalanine) and potentially a key modulator of AA-sensitive mTOR signalling. Coupling of substrate flows through System L and other AA transporters (e.g. System A) may extend the scope for sensing nutrient abundance. Factors influencing AA transporter activity (e.g. hormones) may affect intracellular AA concentrations and hence indirectly mTOR pathway activity. Several AA transporters are themselves regulated by AA availability through ‘adaptive regulation’, which may help to adjust the gain of AA sensing. The substrate-binding sites of AA transporters are potentially direct sensors of AA availability at both faces of the cell surface, and there is growing evidence that AA transporters of the SNAT (sodium-coupled neutral AA transporter) and PAT (proton-assisted AA transporter) families may operate, at least under some circumstances, as transporter-like sensors (or ‘transceptors’) upstream of mTOR.

scholarly journals Substrate-specificity of glutamine transporters in membrane vesicles from rat liver and skeletal muscle investigated using amino acid analogues

1991 ◽  
Vol 278 (1) ◽  
pp. 105-111 ◽  
Author(s):  
S Y Low ◽  
P M Taylor ◽  
A Ahmed ◽  
C I Pogson ◽  
M J Rennie
Keyword(s):  
Skeletal Muscle ◽  
Amino Acid ◽  
Rat Liver ◽  
Membrane Vesicles ◽  
Transport Processes ◽  
System A ◽  
Liver Membrane ◽  
Glutamine Transport ◽  
Fold Excess ◽  
Glutamine Uptake

We investigated the effects of glutamine and histidine analogues on glutamine transport processes in membrane vesicles prepared from rat liver (sinusoidal membrane) and skeletal muscle (sarcolemma). L-[14C]Glutamine is transported in these membranes predominantly by Systems N/Nm (liver and muscle respectively), and to a lesser extent by Systems A and L (e.g. about 60, 20 and 20% of total flux respectively via Systems N, A and L at 0.05 mM-glutamine in liver membrane vesicles). The glutamine anti-metabolites 6-diazo-5-oxo-L-norleucine and acivicin were relatively poor inhibitors of glutamine uptake into liver membrane vesicles (less than 25% inhibition at 20-fold excess) and appeared primarily to inhibit System A activity (i.e. N-methylaminoisobutyric acid-inhibitable glutamine uptake). In similar experiments azaserine (also a glutamine anti-metabolite) inhibited approx. 50% of glutamine uptake, apparently by inhibition of System A and also of System L (i.e. 2-amino-2-carboxybicyclo[2,2,1]heptane-inhibitable glutamine uptake). Glutamate gamma-hydroxamate, aspartate beta-hydroxamate, histidine and N'-methylhistidine were all strong inhibitors of glutamine uptake into liver membrane vesicles (greater than 65% inhibition at 20-fold excess), but neither homoglutamine nor N'-methylhistidine produced inhibition. L-Glutamate-gamma-hydroxamate was shown to be a competitive inhibitor of glutamine transport via System N (Ki approximately 0.6 mM). Glutamine uptake in sarcolemmal vesicles showed a similar general pattern of inhibition as in liver membrane vesicles. The results highlight limits on the substrate tolerance of System N; we suggest that the presence of both an L-alpha-amino acid group and a nitrogen group with a delocalized lone-pair of electrons (amide or pyrrole type), separated by a specific intramolecular distance (C2-C4 chain equivalent), is important for substrate recognition by this transporter.

Regulation of amino acid transporters by glucose and growth factors in cultured primary human trophoblast cells is mediated by mTOR signaling

2009 ◽  
Vol 297 (3) ◽  
pp. C723-C731 ◽  
Author(s):  
S. Roos ◽  
O. Lagerlöf ◽  
M. Wennergren ◽  
T. L. Powell ◽  
T. Jansson
Keyword(s):  
Amino Acid ◽  
Glucose Deprivation ◽  
Mtor Signaling ◽  
Amino Acid Transporters ◽  
Trophoblast Cells ◽  
Human Trophoblast ◽  
System A ◽  
System L ◽  
Igf I ◽  
Human Trophoblast Cells

Inhibition of mammalian target of rapamycin (mTOR) signaling in cultured human primary trophoblast cells reduces the activity of key placental amino acid transporters. However, the upstream regulators of placental mTOR are unknown. We hypothesized that glucose, insulin, and IGF-I regulate placental amino acid transporters by inducing changes in mTOR signaling. Primary human trophoblast cells were cultured for 24 h with media containing various glucose concentrations, insulin, or IGF-I, with or without the mTOR inhibitor rapamycin, and, subsequently, the activity of system A, system L, and taurine (TAUT) transporters was measured. Glucose deprivation (0.5 mM glucose) did not significantly affect Thr172-AMP-activated protein kinase phosphorylation or REDD1 expression but decreased S6 kinase 1 phosphorylation at Thr389. The activity of system L decreased in a dose-dependent manner in response to decreasing glucose concentrations. This effect was abolished in the presence of rapamycin. Glucose deprivation had two opposing effects on system A activity: 1) an “adaptive” upregulation mediated by an mTOR-independent mechanism and 2) downregulation by an mTOR-dependent mechanism. TAUT activity was increased after incubating cells with glucose-deprived media, and this effect was largely independent of mTOR signaling. Insulin and IGF-I increased system A activity and insulin stimulated system L activity, effects that were abolished by rapamycin. We conclude that the mTOR pathway represents an important intracellular regulatory link between nutrient and growth factor concentrations and amino acid transport in the human placenta.

scholarly journals IL-6 stimulates system A amino acid transporter activity in trophoblast cells through STAT3 and increased expression of SNAT2

2009 ◽  
Vol 297 (5) ◽  
pp. C1228-C1235 ◽  
Author(s):  
H. N. Jones ◽  
T. Jansson ◽  
T. L. Powell
Keyword(s):  
Amino Acid ◽  
Protein Expression ◽  
Nutrient Transport ◽  
Amino Acid Transporter ◽  
Amino Acid Transporters ◽  
Trophoblast Cells ◽  
System A ◽  
Tnf Α ◽  
Gene And Protein Expression ◽  
Acid Transporter

Changes in placental nutrient transport are closely associated with abnormal fetal growth. However, the molecular mechanisms underlying the regulation of placental amino acid transporters are unknown. We demonstrate that physiological concentrations of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α stimulate the activity of amino acid transporter system A, but not system L, in cultured human primary trophoblast cells. Both cytokines increased the gene and protein expression of the Na+-coupled neutral amino acid transporter (SNAT)2 isoform and upregulated SNAT1 protein expression. IL-6 increased Tyr705 phosphorylation of signal transducer and activator of transcription 3 (STAT3). In cells transfected with small interfering RNA (siRNA) targeting STAT3, the RNA and protein expression of SNAT2, but not SNAT1, was reduced and the stimulating effect of IL-6 on system A activity was abolished. Despite eliciting similar responses in amino acid transport activity and transporter expression, TNF-α effects on system A activity were not mediated through the JAK/STAT pathway. In conclusion, we have identified a novel regulatory pathway involving increased gene expression of the SNAT2 isoform mediated by a STAT-dependent pathway, which links IL-6 to increased activity of system A, a ubiquitously expressed transporter of neutral amino acids. From these new findings, we propose that upregulation of amino acid transporters by cytokines may contribute to increased placental nutrient transport and fetal overgrowth, which are commonly found in pregnancies complicated by maternal diabetes and obesity.

scholarly journals Evidence for allosteric regulation of pH-sensitive System A (SNAT2) and System N (SNAT5) amino acid transporter activity involving a conserved histidine residue

2006 ◽  
Vol 397 (2) ◽  
pp. 369-375 ◽  
Author(s):  
Fiona E. Baird ◽  
Jorge J. Pinilla-Tenas ◽  
William L. J. Ogilvie ◽  
Vadival Ganapathy ◽  
Harinder S. Hundal ◽  
...  
Keyword(s):  
Amino Acid ◽  
Mammalian Cells ◽  
Ph Sensitivity ◽  
Amino Acid Transporters ◽  
Dependent Manner ◽  
Histidine Residue ◽  
Concentration Dependent Manner ◽  
Histidine Residues ◽  
System A ◽  
External Ph

System A and N amino acid transporters are key effectors of movement of amino acids across the plasma membrane of mammalian cells. These Na+-dependent transporters of the SLC38 gene family are highly sensitive to changes in pH within the physiological range, with transport markedly depressed at pH 7.0. We have investigated the possible role of histidine residues in the transporter proteins in determining this pH-sensitivity. The histidine-modifying agent DEPC (diethyl pyrocarbonate) markedly reduces the pH-sensitivity of SNAT2 and SNAT5 transporters (representative isoforms of System A and N respectively, overexpressed in Xenopus oocytes) in a concentration-dependent manner but does not completely inactivate transport activity. These effects of DEPC were reversed by hydroxylamine and partially blocked in the presence of excess amino acid substrate. DEPC treatment also blocked a reduction in apparent affinity for Na+ (K0.5Na+) of the SNAT2 transporter at low external pH. Mutation of the highly conserved C-terminal histidine residue to alanine in either SNAT2 (H504A) or SNAT5 (H471A) produced a transport phenotype exhibiting reduced, DEPC-resistant pH-sensitivity with no change in K0.5Na+ at low external pH. We suggest that the pH-sensitivity of these structurally related transporters results at least partly from a common allosteric mechanism influencing Na+ binding, which involves an H+-modifier site associated with C-terminal histidine residues.

Regulation of placental amino acid transporter activity by mammalian target of rapamycin

2009 ◽  
Vol 296 (1) ◽  
pp. C142-C150 ◽  
Author(s):  
S. Roos ◽  
Y. Kanai ◽  
P. D. Prasad ◽  
T. L. Powell ◽  
T. Jansson
Keyword(s):  
Amino Acid ◽  
Protein Expression ◽  
Mrna Expression ◽  
Mammalian Target Of Rapamycin ◽  
Amino Acid Transporter ◽  
Amino Acid Transporters ◽  
Mtor Inhibition ◽  
System A ◽  
System L ◽  
Acid Transporter

The activity of placental amino acid transporters is decreased in intrauterine growth restriction (IUGR), but the underlying regulatory mechanisms have not been established. Inhibition of the mammalian target of rapamycin (mTOR) signaling pathway has been shown to decrease the activity of the system L amino acid transporter in human placental villous fragments, and placental mTOR activity is decreased in IUGR. In the present study, we used cultured primary trophoblast cells to study mTOR regulation of placental amino acid transporters in more detail and to test the hypothesis that mTOR alters amino acid transport activity by changes in transporter expression. Inhibition of mTOR by rapamycin significantly reduced the activity of system A (−17%), system L (−28%), and taurine (−40%) amino acid transporters. mRNA expression of isoforms of the three amino acid transporter systems in response to mTOR inhibition was measured using quantitative real-time PCR. mRNA expression of l-type amino acid transporter 1 (LAT1; a system L isoform) and taurine transporter was reduced by 13% and 50%, respectively; however, mTOR inhibition did not alter the mRNA expression of system A isoforms (sodium-coupled neutral amino acid transporter-1, -2, and -4), LAT2, or 4F2hc. Rapamycin treatment did not significantly affect the protein expression of any of the transporter isoforms. We conclude that mTOR signaling regulates the activity of key placental amino acid transporters and that this effect is not due to a decrease in total protein expression. These data suggest that mTOR regulates placental amino acid transporters by posttranslational modifications or by affecting transporter translocation to the plasma membrane.

Tumor-influenced amino acid transport activities in zonal-enriched hepatocyte populations

2000 ◽  
Vol 279 (6) ◽  
pp. G1209-G1218 ◽  
Author(s):  
Alexandra M. Easson ◽  
Timothy M. Pawlik ◽  
Craig P. Fischer ◽  
Jennifer L. Conroy ◽  
Dennis Sgroi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Transport ◽  
Tumor Burden ◽  
Amino Acid Transporters ◽  
Acid Transport ◽  
Specific Amino Acid ◽  
Arginine Uptake ◽  
Mammalian Liver ◽  
Growth System ◽  
Glutamine Uptake

Cancer influences hepatic amino acid metabolism in the host. To further investigate this relationship, the effects of an implanted fibrosarcoma on specific amino acid transport activities were measured in periportal (PP)- and perivenous (PV)-enriched rat hepatocyte populations. Na+-dependent glutamate transport rates were eightfold higher in PV than in PP preparations but were relatively unaffected during tumor growth. System N-mediated glutamine uptake was 75% higher in PV than in PP preparations and was stimulated up to twofold in both regions by tumor burdens of 9 ± 4% of carcass weight compared with hepatocytes from pair-fed control animals. Excessive tumor burdens (26 ± 7%) resulted in hypophagia, loss of PV-enriched system N activities, and reduced transporter stimulation. Conversely, saturable arginine uptake was enhanced fourfold in PP preparations and was induced twofold only after excessive tumor burden. These data suggest that hepatic amino acid transporters are differentially influenced by cancer in a spatial and temporal manner, and they represent the first report of reciprocal zonal enrichment of system N and saturable arginine uptake in the mammalian liver.

Na+-dependent neutral amino acid transporters A, ASC, and N of the blood-brain barrier: mechanisms for neutral amino acid removal

2004 ◽  
Vol 287 (4) ◽  
pp. E622-E629 ◽  
Author(s):  
Robyn L. O'Kane ◽  
Juan R. Viña ◽  
Ian Simpson ◽  
Richard A. Hawkins
Keyword(s):  
Amino Acid ◽  
Blood Brain Barrier ◽  
Functional Organization ◽  
Extracellular Fluid ◽  
Neutral Amino Acid ◽  
Brain Barrier ◽  
Amino Acid Transporters ◽  
System A ◽  
Blood Brain ◽  
Voltage Dependent

Four Na+-dependent transporters of neutral amino acids (NAA) are known to exist in the abluminal membranes (brain side) of the blood-brain barrier (BBB). This article describes the kinetic characteristics of systems A, ASC, and N that, together with the recently described Na+-dependent system for large NAA (Na+-LNAA), provide a basis for understanding the functional organization of the BBB. The data demonstrate that system A is voltage dependent (3 positive charges accompany each molecule of substrate). Systems ASC and N are not voltage dependent. Each NAA is a putative substrate for at least one system, and several NAA are transported by as many as three. System A transports Pro, Ala, His, Asn, Ser, and Gln; system ASC transports Ser, Gly, Met, Val, Leu, Ile, Cys, and Thr; system N transports Gln, His, Ser, and Asn; Na+-LNAA transports Leu, Ile, Val, Trp, Tyr, Phe, Met, Ala, His, Thr, and Gly. Together, these four systems have the capability to actively transfer every naturally occurring NAA from the extracellular fluid (ECF) to endothelial cells and thence to the circulation. The existence of facilitative transport for NAA (L1) on both membranes provides the brain access to essential NAA. The presence of Na+-dependent carriers on the abluminal membrane provides a mechanism by which NAA concentrations in the ECF of brain are maintained at ∼10% of those of the plasma.

Involvement of sodium-coupled neutral amino acid transporters (system A) in l-proline transport in the rat retinal pericytes

2020 ◽  
Vol 35 (5) ◽  
pp. 410-416
Author(s):  
Nobuyuki Zakoji ◽  
Kosuke Tajima ◽  
Daisuke Yoneyama ◽  
Shin-ichi Akanuma ◽  
Yoshiyuki Kubo ◽  
...  
Keyword(s):  
Amino Acid ◽  
Neutral Amino Acid ◽  
Amino Acid Transporters ◽  
Proline Transport ◽  
System A ◽  
Retinal Pericytes

scholarly journals Localization and Functional Relevance of System A Neutral Amino Acid Transporters in Cultured Hippocampal Neurons

2002 ◽  
Vol 277 (12) ◽  
pp. 10467-10473 ◽  
Author(s):  
Simona Armano ◽  
Silvia Coco ◽  
Alberto Bacci ◽  
Elena Pravettoni ◽  
Ursula Schenk ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hippocampal Neurons ◽  
Neutral Amino Acid ◽  
Amino Acid Transporters ◽  
System A ◽  
Functional Relevance ◽  
Cultured Hippocampal Neurons
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