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PubMed1978

Effect of thyrotoxicosis on gluconeogenesis from alanine in the perfused rat liver.

The influence and mechanism of action of T4 treatment on hepatic gluconeogenesis from alanine was studied in isolated rat livers. Conversion of alanine into glucose was increased markedly in livers of thyrotoxic rats compared to that in normal rats. Estimation of metabolic intermediates of the gluconeogenic pathway showed that T4 treatment produced forward cross-over between pyruvate and phosphoenolpyruvate, which suggests that this point is a control site. Alanine transport into the liver cells was apparently active since the alanine level was higher within the hepatocytes than in the extracellular space. Furthermore, T4 treatment stimulated the transport of alanine into the liver cells. alpha-Aminoisobutyric acid uptake was significantly higher by liver of thyrotoxic animals than of normal rats. The hepatic level of cAMP was also higher in experimental livers than control livers. These studies suggest that T4 stimulates hepatic gluconeogenesis from alanine and the underlying mechanism involves an increase in both the transport of amino acid into the liver cell and the conversion pyruvate to phosphoenolpyruvate.

Alanine↗
PubMed1989

Regulation of amino acid transport in rat and human thyroid cells.

To clarify the role of insulin, IGF-I and TSH in thyroid cell regulation, their effects on amino acid transport were studied separately. These effects were noted and compared using both the Wistar rat thyroid cell line and human thyroid cell cultures. Insulin, IGF-I and TSH were able independently to induce the radiolabelled alpha-aminoisobutyric acid transport within the rat thyroid cells: TSH stimulated the amino acid transport in rat thyroid cells in a dose-dependent way from 1 pmol/l to 10 nmol/l. Similarly, insulin increased amino acid transport significantly from 0.17 nmol/l up to 0.17 mumol/l and IGF-I from 0.13 pmol/l up to 0.13 mumol/l. The combined effects of insulin and TSH on amino acid transport were equal to the theoretical sum of the activities, whereas those of IGF-I and TSH were greater than the theoretical one. When human thyroid cell cultures were used, a significant increase of labelled amino acid transport was induced by TSH, i.e. from 0.1 pmol/l to 10 pmol/l; IGF-I stimulated amino acid transport in a range from 0.13 pmol/l to 13 pmol/l, under the same conditions. Conversely, only large doses of insulin, i.e. 1.7 nmol/l, were able weakly to stimulate amino acid transport. When submaximal TSH and IGF-I doses were co-incubated in human thyroid cells, an additive effect on amino acid transport was observed.

Adult↗
PubMed1977

A reassessment of decreased amino acid accumulation by Ehrlich ascites tumor cells in the presence of metabolic inhibitors.

This study was undertaken to examine the mechanism by which metabolic inhibition reduces amino acid active transport in ehrlich ascites tumor cells. At 37 degrees C the metabolic inhibitor combination 0.1 mM 2,4-dinitrophenol (DNP) + 10 mM 2- deoxy-D-glucose (DOG) reduced the cell ATP concentration to 0.10- 0.15 mM in less than 5 min. This inhibition was associated with a 20.6 percent +/- 6.4 percent (SD) decrease in the initial influx of alpha-aminoisobutyric acid (AIB), and a two- to fourfold increase in the unidirectional efflux. These effects could be dissociated from changes in cell Na(+) or K(+) concentrations. Cells incubated to the steady state in 1.0-1.5 mM AIB showed an increased steady-state flux in the presence of DNP + DOG. Steady- state fluxes were consistent with trans-inhibition of AIB influx and trans-stimulation of efflux in control cells, but trans- stimulation of both fluxes in inhibited cells. In spite of the reduction of the cell ATP concentration to less than 0.15 mM and greatly reduced transmembrane concentration gradients of Na(+) and K(+), cells incubated to the steady state in the presence of the inhibitors still established an AIB distribution ration 13.8 +/- 2.6. The results are interpreted to indicate that a component of the reduction of AIB transport produced by metabolic inhibition is attributable to other actions in addition to the reduction of cation concentration gradients. Reduction of cell ATP alone is not responsible for the effects of metabolic inhibition, and both the transmembrane voltage and direct coupling to substrate oxidation via plasma-membrane-bound enzymes must be considered as possible energy sources for amino acid active transport.

Adenosine Triphosphate↗
PubMed1998

Uptake and transport by the ovine placenta of neutral nonmetabolizable amino acids with different transport system affinities.

Placental uptake and transport of three nonmetabolizable amino acids with different reactivities for transport systems were studied in sheep under normal physiologic conditions. Methylaminoisobutyric acid (MeAIB), which has specific affinity for the sodium-dependent A system transporters, demonstrated placental concentrative uptake from the uterine and the umbilical circulations, but virtually no transport from mother to fetus. By contrast, aminoisobutyric acid (AIB) and aminocyclopentane-1-carboxylic acid (ACP), which have affinity for both sodium-dependent and sodium-independent transporters, demonstrated both concentrative uptake and transport from mother to fetus. ACP transport rate to the fetus was approximately twice the AIB transport rate. It is concluded that a neutral amino acid which interacts almost exclusively with the weakly reversible system A transporters may be transported rapidly into the placenta and may attain high concentrations within this organ but cannot escape from placenta to fetus down its own concentration gradient because the exit route is controlled by reversible amino acid transporters at the fetal surface of the placenta. Conversely, high affinity for reversible Na-independent transporters may be a necessary condition for the rapid transport of an amino acid from placenta to fetus.

ATP-Binding Cassette Transporters↗
PubMed1981

Kinetics of and rate equations for the uptake of alpha-amino-isobutyric aicd and gamma-aminobutyric acid by mouse brain slices incubated in a glucose-free medium containing pyruvate as the energy source.

Mouse cerebrum slices were incubated in a medium containing pyruvate instead of glucose as the energy source. After a preincubation period alpha-aminoisobutyric acid (AIB) or gamma-aminobutyric acid (GABA) was added, and the rate of uptake by the slices was measured. AIB and GABA are taken up to above their concentration in the medium. Although influx is slower, the rate equation is the same as that for influx from a glucose medium; namely v = Vmax/1 x Kt/S) + kuS, where v = rate of uptake, S = concentration of AIB or GABA in the medium, and Vmax, Kt, and Ku are constants. The equation shows two parallel pathways for concentrative uptake, one saturable and one unsaturable. The uptake systems for AIB and GABA are qualitatively different. The maximum rate of uptake of AIB by the saturable component is the same in both media even though, in the pyruvate medium, AIB is bound less strongly to the 'carriers'. The maximum rate of uptake of GABA by the saturable component is less in the pyruvate medium although GABA is bound somewhat more strongly to the 'carriers'. The temperature coefficients of the kinetic parameters and their corresponding energies were determined for GABA. Going from glucose to pyruvate medium has little effect on the Arrhenius activation energy (Ea) associated with Vmax and the heat of reaction (delta H) associated with Kt but increases Ea associated with Ku by 1140%.

Aminoisobutyric Acids↗
PubMed1980

Characterization of membrane permeability alterations induced in Vero cells by Clostridium perfringens enterotoxin.

Alterations in plasma membrane permeability induced by Clostridium perfringens enterotoxin were studied using Vero (African green monkey kidney) cells which were radioactively labeled with four markers of different molecular size. The markers were alpha-amino[14C]isobutyric acid (Mr 103), 3H-labeled nucleotide (Mr approx. 300), 51Cr label (Mr approx. 3000) and [3H]RNA (Mr>25000). Over a 2h period, enterotoxin caused significant release of aminoisobutyric acid, nucleotides and 51Cr label but not RNA. The effects of enterotoxin on label release were dose- and time-dependent. The rate of release of markers was dependent upon their size. Permeability alterations could be detected within 15 min with a high dose of enterotoxin. Gel chromatography of released material was used to determine that markers of Mr 3000 but not 25000 leaked from permeabilized cells. It was concluded that enterotoxin is producing functional 'holes' of limited size in the membrane. Permeability changes due to enterotoxin treatment differed between confluent and nonconfluent (growing) cells. We propose that the primary action of the enterotoxin is to interact with the plasma membrane and produce functional 'holes' of defined size. The resultant alterations in membrane permeability cause the loss of essential cellular substances which inhibits processes such as macromolecular synthesis and eventually leads to cell deterioration and death.

Aminoisobutyric Acids↗
PubMed1981

Amino acid transport in rat Sertoli cell enriched testes: studies on the mechanism of action of follicle stimulating hormone.

1. The in vivo administration of ovine Follicle Stimulating Hormone (FSH) (15 mu g/rat, 1 h before measurements) enhanced the transport of Alpha [3-14C]-aminoisobutyric acid ([14C]-AIB) in Sertoli cell enriched testes of 10, 15 and 20-day-old rats. The effect was not observed in 5 or 25-day-old rats. 2. Increasing the intracellular concentration of cyclic AMP by means s cholera toxin, exogenous cyclic AMP or 1-methyl-3-isobutylxanthine did not change either the control or the FSH-stimulated uptake of [14C]-AIB. 3. The inhibition of glycoprotein synthesis by tunicamycin decreased the uptake of [14C]-AIB in controls and significantly reduced (24%) the effect of FSH on [14C]-AIB transport in Sertoli cell enriched testes.

Adenylyl Cyclases↗
PubMed1995

Insulin-like growth factor-1 stimulates amino acid uptake by the cultured human placental trophoblast.

Amino acid uptake by the human placenta is known to occur via several transport mechanisms. However, regulation by extracellular factors has received relatively little attention. A recent report by this laboratory characterized the uptake of alpha-aminoisobutyric acid (AIB) stimulated by insulin in the cultured human placental trophoblast. The current study evaluated the effect of insulin-like growth factor-1 (IGF-1) on AIB uptake in cultured human placental trophoblasts. Na(+)-dependent AIB uptake was significantly stimulated by IGF-I in a time-dependent manner, as early as 30 min after hormone exposure. The maximum effect was at 2-4 hr of continuous exposure to IGF-I and the stimulation was dependent upon IGF-1 concentration approaching maximal stimulation at 50 ng.ml-1. AIB uptake was inhibited by increasing concentrations of alpha-(methylamino)isobutyric acid (MeAIB). Approximately 75% of basal (unstimulated) Na(+)-dependent AIB uptake was inhibited by MeAIB. The IGF-1-stimulated increment above basal AIB uptake was completely inhibited by MeAIB. IGF-1 increased the maximum uptake velocity but not Km. Using equimolar concentrations, stimulation was greater with IGF-1 than with IGF-2. Stimulation by IGF-1, but not insulin, was inhibited by anti-IGF-1 receptor antibody, indicating mediation via the IGF-1 receptor. H7, a nonspecific inhibitor of serine-threonine kinase, inhibited IGF-1-dependent stimulation of AIB uptake. In addition, calphostin C (a specific inhibitor of protein kinase C), but not H89 (a specific inhibitor of protein kinase A), inhibited the IGF-1 action. This study further characterizes regulated amino acid uptake by the human placental trophoblasts and demonstrates that the Na(+)-dependent component of AIB uptake is stimulated by physiologic concentrations of IGF-1.

Aminoisobutyric Acids↗
PubMed1987

Effect of endotoxic shock on skeletal muscle intracellular electrolytes and amino acid transport.

Soleus muscle intracellular electrolytes and alpha-aminoisobutyric acid (AIB) uptake and its regulation by insulin were investigated during endotoxic shock in vivo. Fasted rats (90 g) were injected with [14C]AIB (1-10 mg/kg, iv) and Salmonella enteritidis endotoxin (20 mg/kg, iv) or saline and killed 1-5 h later. AIB uptake into muscle was corrected for uptake into extracellular space (measured as insulin distribution in muscle in vivo) and expressed as [AIB]/[AIB] ratios to assess active transport. The maximum level of active AIB cell transport by extracellular endotoxic muscles [3.3 +/- 0.2 (SE)] was lower than control muscles (4.9 +/- 0.3) at the time when plasma insulin concentration in endotoxic rats (16.8 +/- 2.0 uU/ml) was greater than controls (7.9 +/- 1.7 uU/ml). Insulin-stimulated AIB transport was significantly lower in endotoxic muscles (from a basal value of 3.3 +/- 0.2 to 4.4 +/- 0.5, 5.0 +/- 0.3, and 4.9 +/- 0.3 at 125, 250, and 500 mU/kg intravenous insulin, respectively) than in control muscles (from 4.9 +/- 0.3 to 5.7 +/- 0.2, 8.0 +/- 0.4, and 10.8 +/- 0.8). The intracellular electrolyte concentrations in endotoxic soleus muscles ([Na] = 15.87 +/- 0.9, [K] = 145 +/- 1.7, [Cl] = 14.61 +/- 0.9) were substantially altered when compared with control muscles ([Na] = 9.33 +/- 1.1, [K] = 164 +/- 1.5, [Cl] = 4.1 +/- 0.6) 5 h postinjection. The membrane potential, estimated from chloride equilibrium potential was lower in endotoxic muscles (-52.7 +/- 1.6 mV) when compared with control muscles (-89 +/- 3.5 mV).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1981

Gyrate atrophy of the choroid and retina. Biochemical considerations and experience with an arginine-restricted diet.

Ornithine-delta-aminotransferase deficiency is the primary biochemical defect in gyrate atrophy of the choroid and retina and results in the characteristic accumulation of ornithine. An additional consequence of this inborn error is that arginine, the precursor of ornithine, becomes an essential amino acid. Therefore, to reduce the accumulated ornithine, we placed nine gyrate atrophy patients on an arginine-restricted diet. Plasma ornithine decreased by 50 to 85% within one month. Orally administered, alpha-aminoisobutyric acid facilitated the reduction in ornithine by augmenting renal losses. Over the long term, three patients have maintained near normal plasma ornithine concentrations from 4 to 32 months. Two patients have maintained less striking reductions in ornithine, and four have either been poorly controlled or have terminated the diet. Urinary losses of arginine and ornithine in gyrate atrophy patients with high or low plasma ornithine concentrations are less than 50% of the estimated arginine intake. This observation suggests that the bulk of ingested arginine is somehow metabolized despite the severe reduction in ornithine-delta-aminotransferase activity.

Adolescent↗
PubMed1976

Induction and decay of glucagon-induced amino acid transport in primary cultures of adult rat liver cells: paradoxical effects of cycloheximide and puromycin.

Liver parenchymal cells were isolated from adult rats and cultured in collagen-coated plastic petri dishes in serum-free medium. Glucagon induced 4- to 5-fold increases in alpha-aminoisobutyric acid (AIB) transport within 6 hr. Dexaemthasone had no direct effect on AIB transport but greatly potentiated the induction by glucagon ("permissive effect"). Levels of 3':5'-cyclic AMP increased 30- to 100-fold within 30 min after glucagon addition to cultures that had been treated with dexamethasone, and dibutyryl cyclic AMP mimicked the glucagon induction of AIB transport. Additionally, dexamethasone exerted a "permissive" effect on induction of AIB transport by dibutyryl cyclic AMP, whereas the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine induced AIB transport only in cultures that had been treated with dexamethasone. Induction of AIB transport was not dependent upon the continued presence of glucagon, but induced AIB transport activity decayed to uninduced levels within 3-4 hr after glucagon removal. The protein syntesis inhibitors puromycin and cycloheximide inhibited both induction and decay of glucagon induced AIB transport, but had a stabilizing effect if added once induction or decay had commenced. Unlike cycloheximide, the inhibitory effect of puromycin on the glucagon induction of AIB transport was reversible.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1984

Patterns of electrochemical proton gradient formation by membrane vesicles from an obligately acidophilic bacterium.

Isolated membrane vesicles from the obligately acidophilic bacterium Bacillus acidocaldarius generated an electrochemical gradient of protons (delta mu- H+) upon energization with ascorbate-phenazine methosulfate at pH 6.0 or 3.0. At pH 6.0, there was little or no transmembrane pH gradient (delta pH), but a transmembrane electrical potential (delta psi) of ca. -77 mV, positive out, was observed. At pH 3.0, a delta pH equivalent to - 100 mV, acid out, and a delta psi of -73 mV, positive out, were observed upon energization. The total magnitude of the delta mu- H+ was higher than that of whole cells at acid pH, but the very large delta pHs and the reversed delta psi s, i.e., inside positive, that are typical of acidophile cells were not observed in the vesicles. The vesicles exhibited energy-dependent accumulation of alpha-aminoisobutyric acid that was inhibited by both nigericin and valinomycin (plus K+) at pH 3.0 but was inhibited little by nigericin at pH 6.0.

Aminoisobutyric Acids↗
PubMed1981

Growth inhibitory protein(s) in the 3T3 cell plasma membrane. Partial purification and dissociation of growth inhibitory events from inhibition of amino acid transport.

It has been reported previously that a plasma membrane-enriched fraction from 3T3 cells arrests the growth of sparse 3T3 cells early in the G1 phase of growth (Whittenberger et al., '78, '79). Addition of membranes to sparse 3T3 cells also results in a decrease of the rate of transport of alpha-aminoisobutyric acid (Lieberman et al., '79). We have partially purified the growth-inhibitory proteins from plasma membrane of 3T3 cells. These growth-inhibitory proteins behave as intrinsic membrane proteins and do not require membrane lipids for activity. The partially purified proteins arrest cell growth without affecting the rate of alpha-aminoisobutyric transport; thus, inhibition of both transport and cell growth are not obligatorily coupled events.

Aminoisobutyric Acids↗
PubMed1990

Protein kinase C activators selectively inhibit insulin-stimulated system A transport activity in skeletal muscle at a post-receptor level.

We have investigated the role of phorbol esters on different biological effects induced by insulin in muscle, such as activation of system A transport activity, glucose utilization and insulin receptor function. System A transport activity was measured by monitoring the uptake of the system A-specific analogue alpha-(methyl)aminoisobutyric acid (MeAIB), by intact rat extensor digitorum longus muscle. The addition of 12-O-tetradecanoylphorbol 13-acetate (TPA, 0.5 microM) for 60 or 180 min did not modify basal MeAIB uptake by muscle, suggesting that insulin signalling required to stimulate MeAIB transport does not involve protein kinase C activation. However, TPA added 30 min before insulin (100 nM) markedly inhibited insulin-stimulated MeAIB uptake. The addition of polymyxin B (0.1 mM) or H-7 (1 mM), protein kinase C inhibitors, alone or in combination with TPA leads to impairment of insulin-stimulated MeAIB uptake. This paradoxical pattern is incompatible with a unique action of Polymyxin B or H-7 on protein kinase C activity. Therefore these agents are not suitable tools with which to investigate whether a certain insulin effect is mediated by protein kinase C. TPA did not cause a generalized inhibition of insulin action. Thus both TPA and insulin increased 3-O-methylglucose uptake by muscle, and their effects were not additive. Furthermore, TPA did not modify insulin-stimulated lactate production by muscle. In keeping with this selective modification of insulin action, treatment of muscles with TPA did not modify insulin receptor binding or kinase activities. In conclusion, phorbol esters do not mimic insulin action on system A transport activity; however, they markedly inhibit insulin-stimulated amino acid transport, with no modification of insulin receptor function in rat skeletal muscle. It is suggested that protein kinase C activation causes a selective post-receptor modification on the biochemical pathway by which insulin activates system A amino acid transport in muscle.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1995

Effect of chronic cocaine administration on amino acid uptake in rat placental membrane vesicles.

This study evaluated the effects of chronic exposure to cocaine during pregnancy on amino acid uptake in placental membrane vesicles. Pregnant rats received 62 mg/kg of cocaine hydrochloride by intraperitoneal (IP) injection as a divided daily dose on gestation days 8-19 inclusive. Fetal body weights were significantly decreased by 19% in the cocaine group, while placental weights were unchanged. Placental apical membrane vesicles were prepared from control and cocaine-treated animals, and marker enzyme enrichments for alkaline phosphatase and [3H]-dihydroalprenolol binding did not differ between cocaine and control groups. Rates of uptake (10 sec) of selected radiolabeled amino acids were measured utilizing a rapid filtration technique. Na(+)-dependent apical membrane [3H]-glutamine transport (50 microM) was reduced by 95% (p < 0.05) in cocaine-treated compared to control placentas. Uptake of 50 microM [3H]-methyl aminoisobutyric acid (MeAIB) into apical membranes was also decreased by 43% (p < 0.05) in cocaine membranes. Na(+)-independent [3H]-arginine transport (10 microM), however, did not differ between control or cocaine-treated groups. In summary, chronic cocaine administration selectively inhibited the transport of glutamine and MeAIB into apical membrane vesicles, but had minimal effect on arginine transport. We postulate that this diminution in uptake may contribute to the fetal growth retardation noted in our model.

Aminoisobutyric Acids↗
PubMed1985

Wheat germ agglutinin and concanavalin A inhibit the response of human fibroblasts to peptide growth factors by a post-receptor mechanism.

The effect of plant lectins on amino acid uptake and DNA synthesis in cultured human skin fibroblasts stimulated by various peptide mitogens was studied. Wheat germ agglutinin (WGA), at a concentration of 5 micrograms/ml, which by itself had little effect on 3H-aminoisobutyric acid (AIB) uptake, markedly inhibited stimulation of 3H-AIB uptake by somatomedin-C, insulin, epidermal growth factor (EGF) and platelet-derived growth factor. This inhibition could not be overcome by increasing the concentration of peptide added. Neither WGA nor concanavalin A (Con A) significantly affected basal 3H-thymidine incorporation. However both lectins, at concentrations of 5-20 micrograms/ml, decreased EGF- and insulin-stimulated DNA synthesis while succinyl Con A, a divalent lectin derivative, did not. The inhibitory effects of lectins on mitogenic stimulation were reversed by alpha-methyl mannose (Con A) or N-acetylglucosamine (WGA), and were not due to a reduction in the binding of growth factors to their receptors. It is concluded that certain lectins noncompetitively inhibit the response of human fibroblasts to multiple peptide mitogens at the post-receptor level, possibly by interfering with lateral mobility and aggregation of mitogen-receptor complexes.

Acetylglucosamine↗
PubMed1983

Glucagon resistance of hepatoma cells. Evidence for receptor and post-receptor defects.

Of all available liver cells in culture, only primary cultured hepatocytes are known to respond to glucagon in vitro. In the present study we investigated whether glucagon could stimulate amino acid transport and tyrosine aminotransferase (TAT;EC 2.6.1.5) activity (two well-characterized glucagon effects in the liver) in Fao cells, a highly differentiated rat hepatoma cell line. We found that glucagon had no effect on transport of alpha-aminoisobutyric acid (AIB; a non-metabolizable alanine analogue) nor on TAT activity, even though both activities could be fully induced by insulin [2-fold and 3-fold effects for AIB transport and TAT activity, respectively, after 6h; EC50 (median effective concentration) = 0.3 nM], or by dexamethasone (5-8-fold effects after 20 h; EC50 = 2 nM). Analysis of [125I]iodoglucagon binding revealed that Fao cells bind less than 1% as much glucagon as do hepatocytes, whereas insulin binding in Fao cells was 50% higher than in hepatocytes. The addition of dibutyryl cyclic AMP, which fully mimics the glucagon stimulation of both AIB transport and TAT activity in hepatocytes, induced TAT activity in Fao cells (a 2-fold effect at 0.1 mM-dibutyryl cyclic AMP) but had no effect on AIB transport. Cholera toxin stimulated TAT activity to the same extent as did dibutyryl cyclic AMP. These results indicate that the lack of glucagon responsiveness in cultured hepatoma cells results from both a receptor defect and, for amino acid transport, an additional post-receptor defect. Moreover, the results show that amino acid transport and TAT activity, which appeared to be co-induced by insulin or by dexamethasone in these cells, respond differently to cyclic AMP. This suggests that different mechanisms are involved in the induction of these activities by glucagon in liver.

Aminoisobutyric Acids↗
PubMed1980

Sodium ion-substrate symport in a marine bacterium.

Anaerobic suspensions of Alteromonas haloplanktis accumulated alpha-aminoisobutyric acid, by a sodium-dependent process, in response to an artificially imposed membrane potential in the presence or absence of a transmembrane chemical gradient of sodium. These results suggest that the transport of alpha-aminoisobutyrate by this organism occurs via Na+-substrate symport.

Aminoisobutyric Acids↗