Glutamine Uptake by Neurons: Interaction of Protons with System A Transporters

Chaudhry, Farrukh A.; Schmitz, Dietmar; Reimer, Richard J.; Larsson, Peter H.; Gray, Andrew T.; Nicoll, Roger A.; Kavanaugh, Michael P.; Edwards, Robert H.

doi:10.1523/jneurosci.22-01-00062.2002

Cited by 190 publications

(202 citation statements)

References 33 publications

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“…Consistently, our data indicated that proliferation of MDA-MB-231(SA) cells in serine-free conditions was strongly inhibited by PSAT1 knockdown. Serine is transported in and out of cells via amino acid transporters: the Na+-dependent transporters ASCT1 (SLC1A4) and ASCT2 (SLC1A5) [21,22], the system A transporters SA1 (SLC38A1) and SA2 (SLC38A2) [23] and the Na+-independent alanineserine-cysteine transporter 1 (Asc-1 (SLC7A10)) [24]. One of these transporters, In addition to cell proliferation, our data suggest that enhanced serine biosynthesis may promote other aspects in the metastatic cascade.…”

Section: Discussionmentioning

confidence: 99%

Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis

Pollari

Käkönen

Edgren

et al. 2010

Breast Cancer Res Treat

228

196

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Since bone metastatic breast cancer is an incurable disease, causing significant morb idity and mortality, understanding of the underlying molecu lar mechanisms would be h ighly valuable. Here, we describe in v itro and in v ivo evidence for the importance of serine biosynthesis in the metastasis of breast cancer to bone. We first characterized the bone metastatic propensity of the MDA-MB-231(SA) cell line variant as compared to the parental MDA-MB-231 cells by radiographic and histological observations in the inoculated mice. Geno me -wide gene exp ression profiling of th is isogenic cell line pair revealed that all the three genes involved in the L-serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) were upregulated in the highly metastatic variant. This pathway is the primary endogenous source for L-serine in mammalian t issues. Consistently, we observed that the proliferat ion of MDA -MB-231(SA) cells in serine-free conditions was dependent on PSAT1 exp ression. In addition, we observed that L-serine is essential for the fo rmation of bone resorbing human osteoclasts and may thus contribute to the vicious cycle of osteolytic bone metastasis. High expression of PHGDH and PSAT1 in primary breast cancer was significantly associated with decreased relapse-free and overall survival of patients and malignant phenotypic features of breast cancer. In conclusion, high expression of serine biosynthesis genes in metastatic breast cancer cells and the stimulating effect of L-serine on osteoclastogenesis and cancer cell pro liferat ion indicate a functionally critical role for serine biosynthesis in bone metastatic breast cancer and thereby an opportunity for targeted therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis

Pollari

Käkönen

Edgren

et al. 2010

Breast Cancer Res Treat

228

196

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“…[42][43][44][45] Very recently, Ju et al 46) demonstrated that protonation/deprotonation of two histidine residues on the extracellular domain regulated glycine transport activity via one isoform of glycine transporters (GLYT1), which are members of the Na ϩ /Cl Ϫ -dependent neurotransmitter transporter family. Furthermore, they showed that zinc noncompetitively inhibits the glycine transport activity with its chelating with two histidine residues, of which one is overlapped with proton binding sites.…”

Section: Discussionmentioning

confidence: 99%

The Extracellular pH Dependency of Transport Activity by Human Oligopeptide Transporter 1 (hPEPT1) Expressed Stably in Chinese Hamster Ovary (CHO) Cells: A Reason for the Bell-Shaped Activity versus pH

Fujisawa

Tateoka

Nara

et al. 2006

Biological & Pharmaceutical Bulletin

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It has been estimated that more than 80% of amino acids found in the intestinal lumen after a protein meal are in the form of small peptides rather than free amino acids.1) Therefore, a majority of protein digestion products are obligatorily absorbed via an intestine oligo-peptide transporter called PEPT1. Of interest, PEPT1 also mediates the absorption of a huge number of pharmacologically important compounds including peptidomimetic drugs, 2,3) such as oral b-lactam antibiotics, 4-6) ACE-inhibitors like captopril, 7) or the peptidase inhibitor bestatine 8) and even compounds without an obvious peptide bond or equivalent, 9) such as d-amino levulinic acid.10) This surprisingly high tolerance for structural diversity of the substrate by PEPT1 has been expected to be used as a channel to increase the intestinal absorption of poorly absorbable drugs. 11)The transport of substrates via PEPT1 is coupled to the downward movement of a proton in accordance with its electrochemical gradient. 2,3,12) It has been demonstrated in intestinal membrane vesicles, 4,13,14) Xenopus oocytes 15) and culture cells 16) that the transport activity of PEPT1 shows a bellshaped pH dependence with an optimal pH 5.5 to 6.0. This optimal pH is physiologically collaborated with an acidic unstirred water layer (pH 5.5-6.0) in the intestinal lumen. 1,17) Hence, PEPT1 can function most efficiently in epithelial cells of the small intestine.As for the bell-shaped activity of PEPT1 vs. pH, the reason why the transport activity decreases with an increase in pH is obviously the decrease in the driving force of the proton electrochemical potential gradient. On the other hand, why does the activity decrease in a more acidic region although the driving force should increase? To answer this question, we will try to obtain a relationship between the transport activity and extracellular pH. However, there is a problem to be solved: The driving force changes along with the change in extracellular pH. The pH-dependent properties of PEPT1 should be determined without changing the driving force. Here, we employ the experimental condition that the proton concentration gradient across the membrane is dissipated by the addition of monensin and nigericin 18,19) ; then the driving force is solely the membrane potential. To perform this experiment, a cell line is necessary which shows high transport activity. First, we established stably transfected CHO cells which show high transport activities for various substrates with almost the same K m values as those obtained from those of a model human intestine epithelial cell line, Caco-2. [20][21][22] Thus, this CHO cell line over-expressing hPEPT1 (designated as CHO/hPEPT1) is useful and convenient for transport studies of hPEPT1. In the present study, we then examined the pH-dependency of transport activity by hPEPT1 using CHO/hPEPT1 cells. Human oligopeptide transporter (hPEPT1) translocates di/tri-peptide by coupling to movement of proton down the electrochemical gradient. This transporter has the characteristics ...

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“…These system N amino acid transporters mediate the uptake of 1 glutamine molecule with the net uptake of 1 Na + in exchange of a proton. The other members of the SLC38 family, the system A transporters (SNAT1, SNAT2, SNAT4) are not able for countertransport of protons [13][14][15][16]. SNAT3 is highly abundant in liver, kidney, and brain, and expression has also been reported for adipose tissue, pancreas, skeletal muscle, and eye.…”

Section: Introductionmentioning

confidence: 99%

Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

Chan

Busque

Sailer

et al. 2015

Pflugers Arch - Eur J Physiol

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Glutamine, the most abundant amino acid in mammals, is critical for cell and organ functions. Its metabolism depends on the ability of cells to take up or release glutamine by transporters located in the plasma membrane. Several solute carrier (SLC) families transport glutamine, but the SLC38 family has been thought to be mostly responsible for glutamine transport. We demonstrate that despite the large number of glutamine transporters, the loss of Snat3/Slc38a3 glutamine transporter has a major impact on the function of organs expressing it. Snat3 mutant mice were generated by N-ethyl-N-nitrosurea (ENU) mutagenesis and showed stunted growth, altered amino acid levels, hypoglycemia, and died around 20 days after birth. Hepatic concentrations of glutamine, glutamate, leucine, phenylalanine, and tryptophan were highly reduced paralleled by downregulation of the mTOR pathway possibly linking reduced amino acid availability to impaired growth and glucose homeostasis. Snat3-deficient mice had altered urea levels paralleled by dysregulation of the urea cycle, gluconeogenesis, and glutamine synthesis. Mice were ataxic with higher glutamine but reduced glutamate and gamma-aminobutyric acid (GABA) levels in brain consistent with a major role of Snat3 in the glutamine-glutamate cycle. Renal ammonium excretion was lower, and the expression of enzymes and amino acid transporters involved in ammoniagenesis were altered. Thus, SNAT3 is a glutamine transporter required for amino acid homeostasis and determines critical functions in various organs. Despite the large number of glutamine transporters, loss of Snat3 cannot be compensated, suggesting that this transporter is a major route of glutamine transport in the liver, brain, and kidney. ABSTRACTGlutamine, the most abundant amino acid in mammals, is critical for cell and organ functions. Its metabolism depends on the ability of cells to take up or release glutamine by transporters located in the plasma membrane. Several solute carrier (SLC) families transport glutamine, but the SLC38 family has been thought to be mostly responsible for glutamine transport. We demonstrate that despite the large number of glutamine transporters, loss of the Snat3/Slc38a3 glutamine transporter has a major impact on the function of organs expressing it. Snat3 mutant mice were generated by N-ethyl-N-nitrosurea (ENU) mutagenesis and showed stunted growth, altered amino acid levels, hypoglycemia, and died around 20 days after birth. Hepatic concentrations of glutamine, glutamate, leucine, phenylalanine, and tryptophan were highly reduced paralleled by downregulation of the mTOR pathway possibly linking reduced amino acid availability to impaired growth and glucose homeostasis. Snat3 deficient mice had altered urea levels paralleled by dysregulation of the urea cycle, gluconeogenesis, and glutamine synthesis. Mice were ataxic with higher glutamine but reduced glutamate and GABA levels in brain consistent with a major role of Snat3 in the glutamine-glutamate cycle. Renal ammonium excretion ...

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Glutamine Uptake by Neurons: Interaction of Protons with System A Transporters

Cited by 190 publications

References 33 publications

Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis

Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis

The Extracellular pH Dependency of Transport Activity by Human Oligopeptide Transporter 1 (hPEPT1) Expressed Stably in Chinese Hamster Ovary (CHO) Cells: A Reason for the Bell-Shaped Activity versus pH

Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

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