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The uptake of 3-hydroxykynurenine (3HK), a tryptophan metabolite with reported convulsant and cytotoxic properties, has been investigated in a neuronally derived hybrid cell line and in tissue slices prepared from rat brain. In both systems, the observed uptake was temperature-dependent and inhibited in the presence of large neutral amino acids. The apparent Km and Vmax determined for 3HK uptake into N18-RE-105 cells were 1.65 mM and 25.5 nmol/(min x mg protein), respectively. The uptake of 3HK into rat brain slices could be resolved into two components on the basis of their requirements for sodium. Kinetic analyses performed using hippocampal slices revealed a Km of 1.1 mM and Vmax of 18.8 nmol/(h x mg protein) for the sodium-independent process and a Km of 4.8 mM and Vmax of 54.5 nmol/(h x mg protein) for the sodium-dependent process. While sodium-dependent uptake was abolished following treatment with metabolic inhibitors, sodium-independent uptake was only slightly impaired. Sodium-independent uptake was inhibited in the presence of the non-metabolizable amino acids, aminoisobutyric acid (AIB) and aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH), but not by N-methylated amino acid substrates. Sodium-dependent uptake was insensitive to AIB and was completely abolished by BCH. These results indicate that an uptake process for 3HK is present in the mammalian brain, and suggest that the sodium-dependent component of 3HK transport may be mediated by a system which has not previously been described in CNS tissue.
Two groups of new peptaibol-type antibiotics termed cephaibols have been isolated from the fungus Acremonium tubakii, DSM 12774. These 16- or 17-unit straight-chain peptides, whose structures were characterized by amino acid analyses, 2-D NMR experiments, and by mass spectrometric sequencing, have a high content of the unusual amino acids aminoisobutyric acid and isovaline. The principal constituent of the novel peptaibol mixture is cephaibol A, which is formed in abundance in cultures of the wild strain. The striking biological property of cephaibol A is its pronounced anthelmintic action and activity against ectoparasites.
A myo-inositol-related defect in nerve sodium-potassium ATPase activity in experimental diabetes has been suggested as a possible pathogenetic factor in diabetic neuropathy. Because the sodium-potassium ATPase is essential for other sodium-cotransport systems, and because myo-inositol-derived phosphoinositide metabolites regulate multiple membrane transport processes, sodium gradient-dependent amino acid uptake was examined in vitro in endoneurial preparations derived from nondiabetic and 14-d alloxan diabetic rabbits. Untreated alloxan diabetes reduced endoneurial sodium-gradient dependent uptake of the nonmetabolized amino acid 2-aminoisobutyric acid by greater than 50%. Administration of an aldose reductase inhibitor prevented reductions in both nerve myo-inositol content and endoneurial sodium-dependent 2-aminoisobutyric acid uptake. Myo-inositol supplementation that produced a transient pharmacological elevation in plasma myo-inositol concentration, but did not raise nerve myo-inositol content, reproduced the effect of the aldose reductase inhibitor on endoneurial sodium-dependent 2-aminoisobutyric acid uptake. Phorbol myristate acetate, which acutely normalizes sodium-potassium ATPase activity in diabetic nerve, did not acutely correct 2-aminoisobutyric uptake when added in vitro. These data suggest that depletion of a small myo-inositol pool may be implicated in the pathogenesis of defects in amino acid uptake in diabetic nerve and that rapid correction of sodium-potassium ATPase activity with protein kinase C agonists in vitro does not acutely normalize sodium-dependent 2-aminoisobutyric acid uptake.
Amino acid transport was studied in primary cultures of parenchymal cells isolated from adult rat liver by a collagenase perfusion technique and maintained as a monolayer in a serum-free culture medium. Amino acid transport was assayed by measuring the uptake of the nonmetabolizable amino acid, alpha-aminoisobutyric acid. Rat liver parenchymal cells transported alpha-aminoisobutyric acid by an energy-dependent Na+-requiring system which displayed Michaelis-Menten kinetics. Addition of insulin to cultured rat liver parenchymal cells resulted in an increased influx of alpha-aminoisobutyric acid which was reflected in a higher initial rate of alpha-aminoisobutyric acid transport as well as an increased accumulation of alpha-aminoisobutyric acid at later time points. Cycloheximide effectively blocked the increase while results with actinomycin D were equivocal. Insulin at concentrations as low as 50 pM was effective in stimulating alpha-aminoisobutyric acid transport while the maximal response was observed at 80 nM.
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Neutral amino acid transport was characterized in human synovial cells. The amino acids tested are transported by all three major neutral amino acid transport systems, that is, A, L, and ASC. The model amino acid 2-aminoisobutyric acid (AIB) was found to be a strong specific substrate for system A in synovial cells. When cells were starved of amino acids, the activity of AIB transport increased, reaching a maximum within 1 h. The stimulation of transport activity was not blocked by cycloheximide and would thus appear to be related to a release from transinhibition. Similarly, the decrease in the activity of AIB transport observed after the addition of alpha-methyl-aminoisobutyric acid (meAIB) appeared to be related to transinhibition. However, using a different approach, that is, amino acid starvation followed by incubation with 10 mM meAIB and transfer to an amino acid-free medium with or without cycloheximide supplementation, a clear increase in AIB uptake, due both to derepression and a release from transinhibition, was observed. Unlike human fibroblasts, the depression of system A in these synovial cells was not serum-dependent. The process of derepression was observed only after preloading with meAIB. Neither AIB nor alanine produced this phenomenon. Moreover, alanine preloading led to a large increase in AIB transport activity due to a release from transinhibition. These observations indicate that the process of derepression and release from transinhibition are specific to the substrates present in the culture medium prior to amino acid starvation.
In androgen-responsive cells, activity of a sodium-dependent transport system for neutral amino acids is shown to be density-dependent, whereas activity of a sodium-independent system is not. Transport of the non-metabolizable amino acid, alpha-aminoisobutyric acid (alpha-aib) was largely sodium-dependent, whereas transport of cycloleucine (cyleu) was by both sodium-dependent and sodium-independent systems. The Km for cyleu transport changed with density because only the sodium-dependent portion of this transport was density-dependent. By contrast, the Vmax for alpha-aib transport changed with density, indicating that either the amount of functional membrane carrier or the activity of the sodium pump was affected.
BACKGROUND: Sepsis has been shown to impair the barrier function and metabolism of the intestine. This study was done to investigate the effect of sepsis on intestinal absorption of proline, leucine, glutamic acid, and aminoisobutyric acid. STUDY DESIGN: Rats (six per group) were studied 24 hours after cecal ligation and puncture (CLP) or six hours after intraperitoneal injection of lipopolysaccharide (LPS). Controls underwent sham laparotomy or saline solution injection. Four 7-cm everted proximal jejunal sacs were prepared from each rat and filled with 800 microL Krebs' bicarbonate buffer containing 100 mumol/L of amino acid. Paired sacs (septic and control) were incubated at 37 degrees C in flasks containing the same solution trace labeled with 3H containing the same solution trace labeled with 3H amino acid. Sac contents were aspirated 60 minutes later and amino acid uptake was determined by scintillation counting. RESULTS: Twenty-four hours after CLP and six hours after LPS administration there was significant impairment in the intestinal absorption of all amino acids studied. Absorption of glutamic acid was the least affected, followed by leucine, aminoisobutyric acid, and proline. CONCLUSIONS: Sepsis impairs the intestinal absorption of amino acids. The magnitude of this defect in absorption differed with the amino acid studied, suggesting that not all transport systems were affected equally. This differential response of transport systems to sepsis appears to be the inverse of what is observed after a period of starvation.
The regulation of growth by the GH-dependent mitogen somatomedin-C (Sm-C) may involve not only changes in circulating levels of Sm-C, but also alterations in cellular sensitivity to Sm-C induced by humoral factors. Glucocorticoids have been reported to enhance the stimulatory effect of Sm-C on DNA synthesis and cell replication in cultured human fibroblasts, but the cellular alteration responsible for this effect was not fully defined. Using an assay for cellular sensitivity to Sm-C based on stimulation of uptake of the amino acid analog aminoisobutyric acid, a 20-h preincubation with 100 nM dexamethasone was found to enhance both the sensitivity and the maximal responsiveness of human fibroblasts to a 3-h incubation with Sm-C. This effect was found using fibroblasts from multiple normal donors of different ages, and dexamethasone was approximately 10-fold more potent than hydrocortisone. The glucocorticoid antagonist RU486 (100 nM) largely reversed the enhancing effect of 100 nM dexamethasone on Sm-C action. Binding of [125I]Sm-C to intact fibroblast monolayers or trypsin-dispersed cells could be increased by 60-80% by glucocorticoid preincubation, and this increase correlated well with enhanced stimulation of [3H]aminoisobutyric acid uptake, suggesting that the enhancement of Sm-C action in glucocorticoid-treated cells may be mediated at the level of the Sm-C receptor.
The effect of a neutral amino acid, 2-aminoisobutyric acid (AIB) on steady state cell volume has been examined in rat renal papillary slices incubated in hyperosmotic media (2,000 mosmol/kg H2O) containing high concentrations of NaCl and urea (thus imitating papillary interstitial fluid in the intact kidney during antidiuresis). Volumes were significantly increased (P less than 0.001) when external AIB was raised from 0.1 to 10 mmol/l. Na+-dependent AIB uptake occurred, and there were net increases in cell contents of Na+ and Cl-. Replacement of Na+ by Li+, but not by other cations, did not influence the effect of AIB concentration on cell volume, but this was abolished when Cl- was replaced by other anions. The effect of AIB was abolished by diphenylamine-2-carboxylate (10(-3) mmol/l), bumetanide (at 1 mmol/l but not 10(-2) mmol/l) and by N,N'-dicyclohexylcarbodiimide (0.5 mmol/l), but not by amiloride (1 mmol/l) or 4-acetamido-4'-iso-thiocyanato-stilbene-2,2'-disulphonic acid (1 mmol/l), and was enhanced by the presence of Ba2+ or quinine (1 mmol/l). The findings are interpreted in terms of an inwardly-directed Na+-amino acid cotransporter, which determines steady-state volume, requires simultaneous entry of Cl- through conductive pathways, and whose effects on cell volume are moderated by K+ efflux through volume-sensitive K+ channels.
Uptake of the nonmetabolizable model amino acid 2-aminoisobutyric acid (= AIB) through the basolateral membrane into epithelial cells was studied in sheep colon stripped of serosa and muscle layers. Only the antiluminal surface of the mucosa was exposed to the incubation medium. Thus AIB entry into epithelial cells could only occur through the basolateral membrane. AIB was taken up by a saturable process against a high concentration gradient. AIB uptake was inhibited by other neutral amino acids but not by sugars. In a low Na+ medium AIB uptake was impaired, indicating that active transport of amino acids through the basolateral membrane of colon epithelial cells is Na+-dependent. In the rat a saturable concentrative uptake of AIB through the basolateral membrane of colon epithelial cells has also been demonstrated. Concentrative uptake of amino acids through the basolateral membranes is probably important for the supply of colon epithelium with amino acids.
Thermus flavus and T. ruber grew optimally at 75 and 60 degrees C, respectively, but transport of monosaccharides (D-quinovose) and amino acids (2-aminoisobutyric acid) had optima about 20 degree C lower. Both transports were active, inhibited by 2,4-dinitrophenol but hardly at all by uranyl(2+) ions. Several transport systems are apparently involved with each class of compounds. Preincubation with glucose curtailed subsequent transport severely. Practical cessation of transport below 35 degrees C may be associated with the rather uniform composition of membrane lipids where iso- and anteiso-C15 and C17 acids are practically the only components.