Recent Advances in Mammalian Amino Acid Transport

Kilberg, Michael S.; Stevens, Bruce R.; Novak, Donald A.

doi:10.1146/annurev.nu.13.070193.001033

Cited by 178 publications

(80 citation statements)

References 81 publications

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“…Because arginine transport is the subject of several reviews over the past few years [163][164][165][166][167][168], we will summarize points most relevant to the present review. In most mammalian cells, arginine requirements are met primarily by uptake of extracellular arginine via specific transporters, such as systems y + , b o,+ , B o,+ or y + L [163,164,168]. Not all transporters are found in every cell type, and activities of specific transporters can be dynamically regulated in response to specific stimuli, such as bacterial endotoxin and inflammatory cytokines [166].…”

Section: Arginine Transportmentioning

confidence: 99%

Arginine metabolism: nitric oxide and beyond

Morris

1998

Biochemical Journal

2,424

2,036

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Arginine is one of the most versatile amino acids in animal cells, serving as a precursor for the synthesis not only of proteins but also of nitric oxide, urea, polyamines, proline, glutamate, creatine and agmatine. Of the enzymes that catalyse rate-controlling steps in arginine synthesis and catabolism, argininosuccinate synthase, the two arginase isoenzymes, the three nitric oxide synthase isoenzymes and arginine decarboxylase have been recognized in recent years as key factors in regulating newly identified aspects of arginine metabolism. In particular, changes in the activities of argininosuccinate synthase, the arginases, the inducible isoenzyme of nitric oxide synthase and also cationic amino acid transporters play major roles in determining the metabolic fates of arginine in health and disease, and recent studies have identified

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Section: Arginine Transportmentioning

confidence: 99%

Arginine metabolism: nitric oxide and beyond

Morris

1998

Biochemical Journal

2,424

2,036

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“…To understand the regulation of gene expression by amino acids at a molecular level, we have studied the regulation of CHOP expression in response to leucine limitation because (i) leucine is an essential amino acid that is poorly utilized by cells during a 16-h incubation period (data not shown), (ii) leucine, which is transported by system L, is rapidly equilibrated through the cell membrane (41,42), and (iii) Marten et al (12) have shown that leucine depletion strongly induces CHOP expression. To test the possibility that leucine concentration can influence CHOP expression, HeLa, HepG2, or Caco-2 cells were incubated for 16 h in medium containing different concentrations of leucine.…”

Section: Induction Of Chop Mrna Expression By Leucine Limitation-mentioning

confidence: 99%

Amino Acid Limitation Induces Expression of CHOP, a CCAAT/Enhancer Binding Protein-related Gene, at Both Transcriptional and Post-transcriptional Levels

Bruhat¹,

Jousse²,

Wang³

et al. 1997

Journal of Biological Chemistry

192

143

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In mammals, plasma concentrations of amino acids are affected by nutritional or pathological conditions. Here we examined the role of amino acid limitation in regulating the expression of CHOP, a CCAAT/enhancer binding protein (C/EBP)-related gene. CHOP protein is capable of interacting with other C/EBPs to modify their DNA binding activities and may function as a negative regulator of these transcription factors. Our data show that leucine limitation in human cell lines leads to induction of CHOP mRNA and protein in a dose-dependent manner. CHOP mRNA induction is rapidly reversed by leucine replenishment. Elevated mRNA levels result from both an increase in the rate of CHOP transcription and an increase in the CHOP mRNA stability. Using a transient expression assay, we show that a promoter fragment, when linked to a reporter gene, is sufficient to mediate the regulation of CHOP expression by leucine starvation in HeLa cells. In addition, we found that decreasing amino acid concentration by itself can induce CHOP expression independently of a cellular stress due to protein synthesis inhibition. Moreover, CHOP expression is induced at leucine concentrations in the range of those observed in blood of protein-restricted animals suggesting that amino acids can participate, in concert with hormones, in the regulation of gene expression.

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“…3) Reconstitution experiments in Xenopus oocytes have demonstrated that the dependence of nitrite production by transfected NOS2 is dependent upon co-transfection and expression of the CAT transporters. 3 4) While other transport systems have been defined in physiologic terms (60,85), the only other cationic amino acid transporters cloned and sequenced to date, D2 (86) and 4F2 (87), are unlikely to have contributed to L-arginine uptake in our cells. D2 expression is limited to the kidney and intestine (86), and the 4F2 transporter has one-tenth the activity of the CAT family of transporters and could not account for the kinetic data in this report (87).…”

Section: Figmentioning

confidence: 99%

Cytokines and Insulin Induce Cationic Amino Acid Transporter (CAT) Expression in Cardiac Myocytes

Simmons

Closs

Cunningham

et al. 1996

Journal of Biological Chemistry

163

106

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Cytokine-dependent production of nitric oxide (NO) by rat cardiac myocytes is a consequence of increased expression of the inducible isoform of nitric oxide synthase (iNOS or NOS2) and, in the presence of insulin, depresses the contractile function of these cells in vivo and in vitro. Experiments reported here show that Llysine, a competitive antagonist of L-arginine uptake, suppressed NO production (detected as nitrite accumulation) by interleukin (IL)-1␤ and interferon (IFN) ␥-pretreated cardiac myocytes by 70%, demonstrating that NO production is dependent on L-arginine uptake. Cardiac myocytes constitutively exhibit a high-affinity Larginine transport system (K m ‫؍‬ 125 M; V max ‫؍‬ 44 pmol/2 ؋ 10 5 cells/min). Following a 24-h exposure to IL-1␤ and IFN␥, arginine uptake increases (V max ‫؍‬ 167 pmol/2 ؋ 10 5 cells/min) and a second low-affinity L-arginine transporter activity appears (K m ‫؍‬ 1.2 mM). To examine the molecular basis for these cytokine-induced changes in arginine transport, we examined expression of three related arginine transporters previously identified in other cell types. mRNA for the high-affinity cationic amino acid transporter-1 (CAT-1) is expressed in resting myocytes and steady-state levels increase by 10-fold following exposure to IL-1␤ and IFN␥. Only cytokine-pretreated myocytes expressed a second high-affinity L-arginine transporter, CAT-2B, as well as a lowaffinity L-arginine transporter, CAT-2A. In addition, insulin, which potentiated cytokine-dependent NO production independent of any change in NOS activity, increased myocyte L-arginine uptake by 2-fold and steadystate levels of CAT-1, but not CAT-2A or CAT-2B mRNA. Thus, NO production by cardiac myocytes exposed to IL-1␤ plus IFN␥ appears to be dependent on the coinduction of CAT-1, CAT-2A, and CAT-2B, while insulin independently augments L-arginine transport through CAT-1. The inducible isoform of nitric oxide synthase (iNOS or NOS2)1 is expressed in a wide variety of cell types including neonatal and adult cardiac myocytes after exposure to inflammatory mediators (1-6). Nitric oxide (NO) production by cardiac myocytes in vitro decreases spontaneous beating rate (a negative chronotropic effect) (5, 7) and the velocity and extent of shortening (a negative inotropic effect) (6 -12), and accelerates the velocity of re-lengthening (a positive lusitropic effect) (13,14). We recently demonstrated that cytokine-induced NO production by adult rat ventricular myocytes (ARVM), and its effect to diminish the inotropic responsiveness of these cells in vitro to the ␤-adrenergic agonist isoproterenol, was insulin-dependent (15). The observation that this effect of insulin was not a consequence of changes in NOS activity suggested that insulin was affecting myocyte NO generation by additional mechanisms that were independent of the extent of increased expression and activity of NOS2 protein. Potential additional sites for regulating cellular NO production include the availability of intracellular arginine and NOS co-factors. Changes in ar...

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Recent Advances in Mammalian Amino Acid Transport

Cited by 178 publications

References 81 publications

Arginine metabolism: nitric oxide and beyond

Arginine metabolism: nitric oxide and beyond

Amino Acid Limitation Induces Expression of CHOP, a CCAAT/Enhancer Binding Protein-related Gene, at Both Transcriptional and Post-transcriptional Levels

Cytokines and Insulin Induce Cationic Amino Acid Transporter (CAT) Expression in Cardiac Myocytes

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