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PubMed1996

Recent advances in the biochemical and molecular biological basis of cystinuria.

PURPOSE: We reviewed the literature describing recent advances in the understanding of the nature of the transport proteins involved in the renal transport of cystine, properties of the solute carrier family 3, member 1 (SLC3A1) gene, which is involved in renal cystine transport, and the mutations reported in this gene, which have been shown to be the causative factor in approximately half of the cases of type I cystinuria studied. MATERIALS AND METHODS: The MEDLINE data base from 1966 to date and the internet online mendelian inheritance in man were searched using cystinuria, cystine crossed with biological transporters and cystine transporter as key words. Selected citations within these references were also reviewed. RESULTS: The SLC3A1 gene has been shown to code for a protein that, when expressed in Xenopus oocytes, confers on these cells the ability to transport cystine, arginine, lysine and ornithine. To date 21 different mutations and 9 polymorphisms have been reported in the SLC3A1 gene isolated from cystinuric patients. CONCLUSIONS: Type I cystinuria appears to be due to mutations in the SLC3A1 gene, while the molecular genetic determinants of types II and III cystinuria remain to be delineated.

Amino Acid Transport Systems, Basic↗

PubMed1973

Basic amino acid transport in Escherichia coli: properties of canavanine-resistant mutants.

A mutant of Escherichia coli strain CanR 22 has been isolated which is resistant to growth inhibition by canavanine, an analogue of arginine. The properties of this strain and of another canavanine-resistant mutant, JC182-5 (isolated by Celis et al. [5]), were studied. The mutation is pleiotropic in that it results in a reduction in the activity of two distinct permeases, the arginine-specific and lysine-arginine-ornithine transport systems. The lesion maps at min 56 of the E. coli linkage map, at or near the argP locus. Although strain CanR 22 excretes arginine, this excretion appears to result from reduced ability to concentrate arginine, rather than the loss of transport ability being the result of excretion. This conclusion is based on findings with a canavanine-resistant strain auxotrophic for arginine, which exhibits transport properties similar to those of the prototrophic strains. Additionally, growth in the presence of arginine or ornithine results in a repression of the activity of the two basic amino acid transport systems. Neither the arginine-specific nor the lysine-arginine-ornithine binding proteins of the mutant cells show significant alterations in terms of amount, physical properties, or kinetic parameters. These observations lead to the proposal of a model for the two basic amino acid transport systems in which two carrier proteins with different specificities interact with a common energy coupling mechanism. A lesion in the gene (or one of the genes) for this coupling mechanism can confer canavanine resistance.

Arginine↗

PubMed2001

Analysis of the genomic organization of the human cationic amino acid transporters CAT-1, CAT-2 and CAT-4.

By screening nucleotide databases, sequences containing the complete genes of the human cationic amino acid transporters (hCATs) 1, 2 and 4 were identified. Analysis of the genomic organization revealed that hCAT-2 consists of 12 translated exons and most likely of 2 untranslated exons. The splice variants hCAT-2A and hCAT-2B use exon 7 and 6, respectively. The hCAT-2 gene structure is closely related to the structure of hCAT-1, suggesting that they belong to a common gene family. hCAT-4 consists of only 4 translated exons and 3 short introns. Exons of identical size and highly homologous to exon 3 of hCAT-4 are present in hCAT-1 and hCAT-2.

Amino Acid Transport System y+↗

PubMed1993

Voltage dependence of facilitated arginine flux mediated by the system y+ basic amino acid transporter.

Two-microelectrode voltage clamp was used to measure membrane currents resulting from flux of cationic amino acids in Xenopus oocytes expressing the cloned dual-function ecotropic murine leukemia virus receptor/system y+ transporter. At membrane potentials ranging from +20 mV to -120 mV, arginine influx obeyed Michaelis-Menten kinetics. At concentrations from 0.01 to 1 mM, influx increased exponentially with membrane hyperpolarization (e-fold increase/-59 mV). Efflux from oocytes preloaded with arginine increased exponentially with depolarization (e-fold increase/+52 mV). Kinetic analysis based on an iso uni uni facilitated transport model suggests that the effect of voltage on steady-state flux arises largely from charge movement across the membrane field during the conformational transition of the unliganded transporter which switches the substrate binding site from one membrane face to the other. This charge movement would facilitate rapid increases in intracellular arginine concentrations in response to hyperpolarization, a property which could play a role in modulating nitric oxide synthesis in some types of cells.

Animals↗

PubMed1989

[Transport processes through the blood-brain barrier].

The existence of the blood-brain barrier is due to tight junctions between endothelial cells preventing the passage of liquid and solute material at the capillary level. Substances can thus pass across the blood-brain barrier if they are lipophilic or if they have transport systems in the membranes of endothelial cells. The luminal membrane brings metabolites needed for the brain function, the abluminal one plays an important part in removing substances from brain, this can happen against a concentration gradient and thus needs energy. Ions are transported differently by the 2 membranes. Sodium and chloride have carriers and potassium is transported very actively by the sodium-potassium ATPase of the abluminal membrane. Blood-brain glucose influx is very important and happens by carrier transport at the 2 membranes. Efflux seems to use the same transport system as the influx. Transport of ketone bodies seems to happen only from blood to brain, the carriers being reversibly used for brain-blood transport of pyruvic and lactic acid. Amino-acid transport is very different on the luminal and abluminal membranes. On the luminal membrane there are 2 transport systems, one for basic amino acids, the other one, the L system, for neutral amino-acids. All neutral amino-acids are transported through the abluminal membrane by the L, A and ASC systems. There exists a system of transport for basic amino-acids, and a very active one for acid amino-acids. Some systems for the transport of hormones, vitamins and for some peptides exist also at the blood-brain barrier which thus plays a very important role in the regulation of brain metabolism.

Amino Acids↗

PubMed1987

Regional amino acid transport into brain during diabetes: effect of plasma amino acids.

Transport of phenylalanine and lysine into the brain was measured in 4-wk streptozotocin-diabetic rats to assess the effect on the neutral and basic amino acid transport systems at the blood-brain barrier. Amino acid concentrations in plasma and brain were also measured. Regional permeability-times-surface area (PS) products and influx were determined using a continuous infusion method and quantitative autoradiography. The PS of phenylalanine was decreased by an average of 40% throughout the entire brain. Influx was depressed by 35%. The PS of lysine was increased by an average of 44%, but the influx was decreased by 27%. Several plasma neutral amino acids (branched chain) were increased, whereas all basic amino acids were decreased. Brain tryptophan, phenylalanine, tyrosine, methionine, and lysine contents were markedly decreased. The transport changes were almost entirely accounted for by the alterations in the concentrations of the plasma amino acids that compete for the neutral and basic amino acid carriers. The reduced influx could be responsible for the low brain content of some essential amino acids, with possibly deleterious consequences for brain function.

Amino Acids↗

PubMed1987

Characteristics of gentamicin uptake in the isolated crista ampullaris of the inner ear of the guinea pig.

The characteristics of aminoglycoside uptake in the inner ear were investigated in the isolated crista ampullaris. The organ was incubated with radiolabeled gentamicin, and the stable, nonexchangeable radioactivity was considered the intracellular pool of the drug. Gentamicin was transported against a concentration gradient, and the resulting tissue to medium ratios ranged from 1.4 to 18.6. Transport was inhibited by reduction in temperature or by the addition of metabolic blockers, indicative of an energy-dependent component. The uptake system showed at least two sites, the first a high-affinity site with a dissociation constant KD = 39 nM and a capacity of n = 0.2 pmole/crista; the second had a KD = 16 microM and a capacity of n = 11 pmoles/crista. Aminoglycosides competed with uptake of gentamicin in the order netilmicin greater than or equal to neomycin greater than tobramycin, and polyamines competed in the order spermine greater than spermidine greater than putrescine; glucosamine and the basic amino acids lysine and asparagine were ineffective, excluding the participation of glucose and basic amino acid transport systems in gentamicin uptake. These results along with direct comparisons with some characteristics of putrescine uptake suggest that aminoglycoside and polyamine transport have common features in the crista ampullaris.

Animals↗

PubMed1985

Ornithine accumulation and metabolism in rat lens.

The non-protein amino acid ornithine is readily accumulated into rat lenses cultured in TC-199 bicarbonate medium. This accumulation, measured by the lens water/lens medium ratios of radiolabeled ornithine, appears to be the result of an apparent energy-dependent basic amino acid transport system. Moreover, competition studies suggest that increased levels of ornithine can depress the concomitant lenticular accumulation of arginine and lysine. Examination of the trichloroacetic acid protein precipitates of these cultured lenses indicates that the radiolabel from ornithine can also be incorporated into lens proteins as proline. This results from the conversion by ornithine aminotransferase (EC 2.6.1.13) of radiolabeled ornithine to delta1-pyrroline-5-carboxylic acid (P5C), which is subsequently converted to proline by P5C reductase (EC 1.5.1.2). This incorporation of radiolabeled into cultured lens proteins is reduced upon addition of either 1mM proline or P5C to the culture medium or inhibited by the addition of the protein synthesis inhibitor, puromycin.

Animals↗

PubMed2003

Pralidoxime iodide (2-pAM) penetrates across the blood-brain barrier.

The in vivo rat brain microdialysis technique with HPLC/UV was used to determine the blood-brain barrier (BBB) penetration of pralidoxime iodide (2-PAM), which is a component of the current nerve agent antidote therapy. After intravenous dosage of 2-PAM (10, 50, 100 mg/kg), 2-PAM appeared dose-dependently in the dialysate; the striatal extracellular/blood concentration ratio at 1 h after 50 mg/kg dosage was 0.093 +/- 0.053 (mean +/- SEM). This finding offered conclusive evidence of the BBB penetration of 2-PAM. We also examined whether the BBB penetration of 2-PAM was mediated by a certain specific transporter, such as a neutral or basic amino acid transport system. Although it was unclear, the neural uptake of 2-PAM was Na+ dependent. The mean BBB penetration by 2-PAM was approximately 10%, indicating the intravenous administration of 2-PAM might be to a degree effective to reactivation of the blocked cholinesterase in the brain.

Amino Acid Transport Systems↗

PubMed1980

Escherichia coli regulatory mutation affecting lysine transport and lysine decarboxylase.

A spontaneous thiosine-resistant mutant of Escherichia coli was shown to have the following characteristics: lowered initial rate of lysine uptake and lowered plateau level of accumulation of exogenous lysine by both the lysine-specific and the general basic amino acid transport systems; altered repressibility of these two lysine transport systems; a derepressed level of lysine decarboxylase; normal growth rate; parental levels of lysyl-transfer ribonucleic acid synthetase and the inducible and constitutive arginine and ornithine decarboxylases. Both the mutant (lysP) and its parent (lysP+) feed a lysine auxotroph when they are plated in proximity on solid medium. However, the feeding response was observable after 1 day less of incubation when the mutant was the feeding strain. Despite the derepressed level of lysine decarboxylase in exponential cultures of the mutant extracts of these cultures had no detectable cadaverine pool. Conjugation experiments established the following gene order: gyrA (formerly nalA) lysP metG his. All thiosine-resistant recombinants assayed showed reduced lysine transport. In many of these recombinants the derepression of lysine decarboxylase was not expressed.

Amino Acids↗

PubMed1987

[Metabolic changes in ischemic brain infarct].

Serum and cerebrospinal fluid (CSF) from 17 patients less than 3 days after brain infarction (measurement 1) and during recovery 7 +/- 2 days after infarction (measurement 2) were analysed for organic acids (energy metabolites, keto acids and amino acids). Clinical parameters improved by 32% over the period of assessment. Only serum pyruvate levels were elevated at both measurement times. Acute infarction was characterized by significant correspondence of serum and CSF concentrations for pyruvate and alpha-oxo-beta-methyl valeric acid which was lost during the recovery period. Amino acids of the L-system were roughly doubled (phenylalanine 7-fold in the CSF); increased concentrations were recorded for amino acids of the basic transport system, while amino acids of the A-system stayed unchanged (with the exception of alpha-amino butyric acid--20-fold in CSF). Except in the case of taurine, serum and CSF amino acid concentrations remained unchanged between the two measurement times. Mutual dependence of CSF and serum amino acid concentrations, existing initially for glycine, valine, leucine, tyrosine, as well as ornithine, lysine and histidine was lost in the recovery phase. This is interpreted as indication of a normalization of the blood-brain barrier.

Acids↗

PubMed2004

Cell signalling-mediating insulin increase of mRNA expression for cationic amino acid transporters-1 and -2 and membrane hyperpolarization in human umbilical vein endothelial cells.

Insulin induces vasodilatation in human subjects and increases L-arginine transport and NO synthesis in human umbilical vein endothelial cells (HUVEC). Cell signalling events associated with insulin effects on activity and mRNA expression of the human cationic amino acid transporters 1 (hCAT-1) and 2B (hCAT-2B) are unknown. L-arginine transport and eNOS activity were determined in HUVEC exposed to insulin. mRNA levels for hCAT-1, hCAT-2B and eNOS were quantitated by real time RT-PCR and endothelial NO synthase (eNOS) protein was identified by Western blot analysis. Intracellular Ca2+, L-arginine and L-citrulline levels, L-[3H]citrulline formation from L-[(3)H]arginine, cGMP formation, nitrite level, ATP release and membrane potential were determined. Insulin increased L-arginine transport and the mRNA levels for hCAT-1 and hCAT-2B and eNOS expression and activity. Insulin also induced membrane hyperpolarization and increased intracellular Ca2+, L-[3H]citrulline, cGMP and nitrite formation. Insulin-mediated stimulation of the L-arginine/NO pathway is thus associated with increased hCAT-1 and hCAT-2B mRNA, and eNOS expression, via mechanisms involving membrane hyperpolarization, mitogen-activated protein kinases p42 and p44, phosphatidylinositol 3-kinase, NO and protein kinase C. We have characterized a cell signalling pathway by which hyperinsulinaemia could lead to vasodilatation in human subjects, and which could have implications in patients in whom plasma insulin levels are altered, such as in diabetes mellitus.

Adenosine Triphosphate↗

PubMed2002

Five novel SLC7A7 variants and y+L gene-expression pattern in cultured lymphoblasts from Japanese patients with lysinuric protein intolerance.

Two distinct human light subunits of the heteromeric amino acid transporter, y+LAT-1 coded by SLC7A7 and y+LAT-2 coded by SLC7A6, are both known to induce transport system y+L activity. SLC7A7 has already been identified as the gene responsible for lysinuric protein intolerance (LPI). We successfully identified five novel SLC7A7 variants (S238F, S489P, 1630delC, 1673delG, and IVS3-IVS5del9.7kb) in Japanese patients with LPI by PCR amplification and direct DNA sequencing. In addition, we performed a semi-quantitative expression analysis of SLC7A7 and SLC7A6 in human tissue. In normal tissue, the gene-expression ratio of SLC7A6 to SLC7A7 was high in the brain, muscle, and cultured skin fibroblasts; low in the kidneys and small intestine; and at an intermediate level in peripheral blood leukocytes, the lungs, and cultured lymphoblasts. The gene-expression ratio of SLC7A6 to SLC7A7 in cultured lymphoblasts was significantly different between normal subjects and LPI patients with R410X and/or S238F, where the relative amount of SLC7A7 mRNA was significantly lower and the relative amount of SLC7A6 mRNA was statistically higher in affected lymphoblasts than in normal cells. Expression of SLC7A7 and SLC7A6 may thus be interrelated in cultured lymphoblasts.

Adolescent↗

PubMed1992

Thialysine-resistant mutants and uptake of lysine in Schizosaccharomyces pombe.

Mutants defective in lysine transport were isolated and characterized. After UV-mutagenesis colonies resistant to thialysine, a toxic analogue of lysine, were isolated and L-lysine uptake into the mutant strains was analyzed. Among the thialysine-resistant strains a group of mutants was found, where the half-saturation constant, KT, of the high-affinity transport system for lysine was higher than in the wild-type, the high-affinity transport system for basic amino acids being specifically affected. This was confirmed by a complementation test in which all the thialysine-resistant strains with a higher KT for lysine uptake belonged to one complementation group. Kinetic and genetic analysis showed that our mutants were identical with can1-1 mutants, showing that a single high-affinity system for the transport of basic amino acids exists in S. pombe.

Arginine↗

PubMed2004

The stimulation of arginine transport by TNFalpha in human endothelial cells depends on NF-kappaB activation.

In human saphenous vein endothelial cells (HSVECs), tumor necrosis factor-alpha (TNFalpha) and bacterial lipopolysaccharide (LPS), but neither interferon gamma (IFNgamma) nor interleukin 1beta (IL-1beta), stimulate arginine transport. The effects of TNFalpha and LPS are due solely to the enhancement of system y+ activity, whereas system y+L is substantially unaffected. TNFalpha causes an increased expression of SLC7A2/CAT-2B gene while SLC7A1/CAT-1 expression is not altered by the cytokine. The suppression of PKC-dependent transduction pathways, obtained with the inhibitor chelerytrhine, the inhibitor peptide of PKCzeta isoform, or chronic exposure to phorbol esters, does not prevent TNFalpha effect on arginine transport. Likewise, ERK, JNK, and p38 MAP kinases are not involved in the cytokine effect, since arginine transport stimulation is unaffected by their specific inhibitors. On the contrary, inhibitors of NF-kappaB pathway hinder the increase in CAT2B mRNA and the stimulation of arginine uptake. These results indicate that in human endothelial cells the activation of NF-kappaB pathway mediates the TNFalpha effects on arginine transport.

Amino Acid Transport Systems, Basic↗

PubMed2005

The acute phase response alters cationic amino acid transporter expression in growing chickens (Gallus gallus domesticus).

The effect of an acute phase response (APR) on cationic amino acid transporter (CAT1-3) mRNA expression in liver, muscle, bursa and thymus was determined in broiler strain chickens. The APR was initiated by injecting Salmonella typhimurium lipopolysaccharide subcutaneously (LPS; 1 mg/kg bw). In Experiment 1, CAT1-3 mRNA expression was determined at multiple time points following LPS administration. LPS increased bursa and liver total and high affinity CAT mRNA expression (P<0.05) and transiently increased pectoralis total CAT mRNA expression (P<0.05). Total CAT mRNA expression in the thymus decreased 7.7-fold from 0 to 8 h after LPS injection (P<0.05). In Experiment 2, fasted chicks were uninjected or LPS-injected. LPS increased total and high affinity CAT mRNA 2-fold in both the bursa and liver (P<0.05) and did not change thymus total and high affinity CAT mRNA expression (P>0.05). LPS increased liver weight only (P<0.05) and did not alter the plasma lysine and arginine concentration (P>0.05). In Experiments 3 and 4, thymocyte proliferation and total protein content were dependent upon the media lysine concentration (P<0.001). The inability of the thymus to compete for lysine and arginine during the APR may limit the ability of thymocytes to develop during infections.

Acute-Phase Reaction↗

PubMed2001

Amino acid permeases in developing seeds of Vicia faba L.: expression precedes storage protein synthesis and is regulated by amino acid supply.

Full length cDNAs encoding three amino acid permeases were isolated from seed-specific libraries of Vicia faba. The predicted proteins VfAAP1, VfAAP3 and VfAAP4 share up to 66% identity among themselves. Functional characterization of VfAAP1 and VfAAP3 in a yeast mutant showed that these permeases transport a broad range of amino acids. However, VfAAP1 had a preference for cysteine and VfAAP3 for lysine and arginine. VfAAP1 was highly expressed in cotyledons at early developmental stages and moderately in other sink tissues. Its peak of expression in cotyledons corresponded to the appearance of storage protein transcripts, suggesting that this transporter fulfills an important role in providing amino acids for storage protein biosynthesis. VfAAP3 was expressed most abundantly in maternal tissues, that is in roots, stems, gynoecia, pods and seed coats at different developmental stages. VfAAP4 transcripts could not be detected by northern hybridization. In situ hybridization showed that VfAAP1 mRNA is distributed throughout cotyledon storage parenchyma cells, but could not be detected in the abaxial epidermal cell layer. It also accumulate in the chlorenchyma and thin-walled parenchyma cells of seed coats. VfAAP1 mRNA levels were lower in cotyledons cultured in the presence of glutamine, whereas expression of a vicilin storage protein gene was up-regulated under similar conditions. Cysteine repressed the expression of the GUS reporter gene under control of the VfAAP1 promoter, suggesting that this transporter is modulated at the transcriptional level. Regulation of amino acid transport in relation to storage protein accumulation is discussed.

Amino Acid Transport Systems↗

PubMed2006

Arginine homeostasis in J774.1 macrophages in the context of Mycobacterium bovis BCG infection.

The competition for L-arginine between the inducible nitric oxide synthase and arginase contributes to the outcome of several parasitic and bacterial infections. The acquisition of L-arginine, however, is important not only for the host cells but also for the intracellular pathogen. In this study we observe that strain AS-1, the Mycobacterium bovis BCG strain lacking the Rv0522 gene, which encodes an arginine permease, perturbs l-arginine metabolism in J774.1 murine macrophages. Infection with AS-1, but not with wild-type BCG, induced l-arginine uptake in J774.1 cells. This increase in L-arginine uptake was independent of activation with gamma interferon plus lipopolysaccharide and correlated with increased expression of the MCAT1 and MCAT2 cationic amino acid transport genes. AS-1 infection also enhanced arginase activity in resting J774.1 cells. Survival studies revealed that AS-1 survived better than BCG within resting J774.1 cells. Intracellular growth of AS-1 was further enhanced by inhibiting arginase and ornithine decarboxylase activities in J774.1 cells using L-norvaline and difluoromethylornithine treatment, respectively. These results suggest that the arginine-related activities of J774.1 macrophages are affected by the arginine transport capacity of the infecting BCG strain. The loss of Rv0522 gene-encoded arginine transport may have induced other cationic amino acid transport systems during intracellular growth of AS-1, allowing better survival within resting macrophages.

Amino Acid Transport Systems, Basic↗