Taurine Uptake Research Articles

Conditionally immortalized syncytiotrophoblast cell lines as new tools for study of the blood-placenta barrier.

Syncytiotrophoblasts play an essential role in restriction of drug delivery through the blood-placenta barrier (BPB). Conditionally immortalized syncytiotrophoblast cell lines, TR-TBTs, were established at gestational day 18 from pregnant transgenic rats (Tg-rats) harboring the temperature-sensitive SV 40 (ts SV40) large T-antigen. TR-TBTs exhibit temperature-sensitive cell growth due to the expression of SV 40 large T-antigen, and thus the cell growth can be regulated by changing the culture temperature. TR-TBTs exhibit typical properties of syncytiotrophoblast cells, such as syncytium-like morphology, the expression of cytokeratins and hormones, and polarized expression of glucose transporter 1 (GLUT1) and GLUT3. TR-TBTs express in vivo influx and efflux transporters, such as taurine transporter (TauT), betaine/GABA transporter (BGT-1), amino acid transporter 2 (ATA2), organic anion transporting polypeptide 2 (oatp2), organic cation/carnitine transporter (OCTN2), P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP/ABCG2). Moreover, TR-TBTs exhibit taurine, GABA, and DHEA-S uptake activity via TauT, BGT-1, and oatp2, respectively. Therefore, TR-TBTs can be used for the analysis of these functions and would be a good in vitro models for investigating carrier-mediated transport functions at the BPB.

Regulation of the cellular content of the organic osmolyte taurine in mammalian cells.

Change in the intracellular concentration of osmolytes or the extracellular tonicity results in a rapid transmembrane water flow in mammalian cells until intracellular and extracellular tonicities are equilibrated. Most cells respond to the osmotic cell swelling by activation of volume-sensitive flux pathways for ions and organic osmolytes to restore their original cell volume. Taurine is an important organic osmolyte in mammalian cells, and taurine release via a volume-sensitive taurine efflux pathway is increased and the active taurine uptake via the taurine specific taurine transporter TauT decreased following osmotic cell swelling. The cellular signaling cascades, the second messengers profile, the activation of specific transporters, and the subsequent time course for the readjustment of the cellular content of osmolytes and volume vary from cell type to cell type. Using Ehrlich ascites tumor cells, NIH3T3 mouse fibroblasts and HeLa cells as biological systems, it is revealed that phospholipase A2-mediated mobilization of arachidonic acid from phospholipids and subsequent oxidation of the fatty acid via lipoxygenase systems to potent eicosanoids are essential elements in the signaling cascade that is activated by cell swelling and leads to release of osmolytes. The cellular signaling cascade and the activity of the volume-sensitive taurine efflux pathway are modulated by elements of the cytoskeleton, protein tyrosine kinases/phosphatases, GTP-binding proteins, Ca2+/calmodulin, and reactive oxygen species and nucleotides. Serine/threonine phosphorylation of the active taurine uptake system TauT or a putative regulator, as well as change in the membrane potential, are important elements in the regulation of TauT activity. A model describing the cellular sequence, which is activated by cell swelling and leads to activation of the volume-sensitive efflux pathway, is presented at the end of the review.

Cortisol and IGF‐1 synergistically up‐regulate taurine transport by the rat skeletal muscle cell line, L6

This study was undertaken to evaluate effects of exercise-induced hormones, cortisol, IGF-1, and beta-endorphin, on the regulation of taurine transport activity in rat skeletal myoblasts, L6 cells. Challenge of L6 cells with cortisol (100 nM) for 24 hrs resulted in a 165% increase in taurine transport activity, 220% increase in Vmax of the taurine transporter, and 55% increase in taurine transporter/ beta-actin mRNA level compared with untreated control cells. Neither IGF-1 (1 approximately 100 nM) nor beta-endorphin (1 approximately 20 nM), added in the incubation medium separately for 24 hrs, affected taurine uptake by L6 cells. However, when cells were co-treated with IGF-1 (10 nM) plus cortisol (100 nM), taurine transport activity (37% increase, p < 0.05), Vmax of the transporter (54%, p < 0.05), and taurine transporter/ beta-actin mRNA level were further increased compared to the value for cells treated with cortisol alone. These results suggest that taurine transport by skeletal muscle cells appear to be synergistically up-regulated during a prolonged exercise via elevated levels of cortisol and IGF-1 in muscle.

Nitric oxide and superoxide impair human placental amino acid uptake and increase Na + permeability: implications for fetal growth

Based on evidence that thiol and tyrosine reagents inhibit some amino acid transporters, we tested the hypothesis that NO- and O 2 −-derived free radicals would impair nutrient uptake by the human placenta. Syncytiotrophoblast microvillous plasma membrane vesicles (MVM) and placental villous fragments were exposed to the drug SIN-1 in the presence or absence of superoxide dismutase (SOD) and hemoglobin (Hb). The uptake of [ 3H]arginine, [ 3H]taurine, and [ 3H]leucine; [ 14C]MeAIB; and 22Na was studied in MVM, whereas the uptake of [ 3H]taurine was examined in villous fragments. Nitrotyrosine formation was assessed by Western blotting and quantified by ELISA. In MVM, SIN-1 caused an inhibition of [ 3H]arginine, [ 3H]taurine, and [ 14C]MeAIB uptake but had no significant effect on equilibrium [ 3H]leucine uptake. These effects were prevented by SOD or Hb, implying that both NO and O 2 − radicals were essential. In contrast, 22Na + uptake was significantly increased, and this effect was prevented by SOD. In villous fragments, SIN-1 impaired Na +-dependent [ 3H]taurine uptake, with no effect on Na +-independent uptake. Increased nitrotyrosine formation was observed in MVM after SIN-1 treatment. Endogenous NO- and O 2 −-derived free radicals may alter human placental nutrient transfer in vivo, with implications for fetal growth.

Effects of culture conditions on taurine uptake by various variants of human endometrial carcinoma cells in culture.

The general properties of the taurine uptake in human endometrial tumoral Ishikawa cells were similar to those usually found in other tissues. Uptake was notably affected by the oxygen pressure, being higher at the physiological pO(2) of the endometrium (40 mm Hg, equivalent to 5% O(2)) compared to that used under standard experimental culture conditions (160 mm Hg or 20% O(2)). Uptake of taurine was also density-dependent in Ishikawa cells and was significantly decreased at confluence. Uptake regulation by PKC driven phosphorylation occurs only in growing cells and not in resting cells. The taurine uptake of three Ishikawa cell lines was very different. The taurine uptake of one of the cell lines was affected by estradiol, probably through a non-genomic pathway, whereas tamoxifen had no effect in all cell lines.

Role of taurine accumulation in keratinocyte hydration.

Epidermal keratinocytes are exposed to a low water concentration at the stratum corneum-stratum granulosum interface. When epithelial tissues are osmotically perturbed, cellular protection and cell volume regulation is mediated by accumulation of organic osmolytes such as taurine. Previous studies reported the presence of taurine in the epidermis of several animal species. Therefore, we analyzed human skin for the presence of the taurine transporter (TAUT) and studied the accumulation of taurine as one potential mechanism protecting epidermal keratinocytes from dehydration. According to our results, TAUT is expressed as a 69 kDa protein in human epidermis but not in the dermis. For the epidermis a gradient was evident with maximal levels of TAUT in the outermost granular keratinocyte layer and lower levels in the stratum spinosum. No TAUT was found in the basal layer or in the stratum corneum. Keratinocyte accumulation of taurine was induced by experimental induction of skin dryness via application of silica gel to human skin. Cultured human keratinocytes accumulated taurine in a concentration- and osmolarity-dependent manner. TAUT mRNA levels were increased after exposure of human keratinocytes to hyperosmotic culture medium, indicating osmosensitive TAUT mRNA expression as part of the adaptation of keratinocytes to hyperosmotic stress. Keratinocyte uptake of taurine was inhibited by beta-alanine but not by other osmolytes such as betaine, inositol, or sorbitol. Accumulation of taurine protected cultured human keratinocytes from both osmotically induced and ultraviolet-induced apoptosis. Our data indicate that taurine is an important epidermal osmolyte required to maintain keratinocyte hydration in a dry environment.

Development of a scintillation proximity assay for analysis of Na +/Cl −-dependent neurotransmitter transporter activity

Human placental choriocarcinoma (JAR) cells endogenously expressing glycine transporter type 1a (GlyT1a) have been cultured in 96-well scintillating microplates to develop a homogenous screening assay for the detection of GlyT1 antagonists. In these microplates uptake of [ 14C]glycine was time dependent and saturable with a Michaelis–Menten constant ( K m ) of 27 ± 3 μM. The GlyT1 transport inhibitors sarcosine, ALX-5407, and Org-24598 were tested and shown to block [ 14C]glycine uptake with expected IC 50 values of 37.5 ± 4.6 μM, 2.8 ± 0.6 nM, and 6.9 ± 0.9 nM, respectively. The [ 14C]glycine uptake process was sensitive to membrane Na + gradient as blockade of membrane Na +/K +-ATPase by ouabain or Na + exchanger by benzamil-disrupted glycine accumulation in JAR cells. Glycine influx was not affected by concentration of dimethyl sulfoxide up to 2%. The versatility of this technological approach was further confirmed by the characterization of a saturable [ 14C]taurine uptake in JAR cells. Taurine transport was of high affinity with a K m of 10.2 ± 1.7 μM and fully inhibited by ALX-5407 (IC 50=522 ± 83 nM). The developed assay is homogenous, rapid, versatile and amenable to automation for the discovery of new neurotransmitter transporter inhibitors.

Inhibition of taurine transport by high concentration of glucose in cultured rat cardiomyocytes

Cultured rat cardiomyocytes were treated with 10, 20, and 30 mmol/L glucose and 30 mmol/L glucose plus protein kinase C (PKC) inhibitor, Chelerythrine. In the 20 and 30 mmol/L glucose-treated cells, taurine contents reduced by 15% and 27% ( P < .05), respectively, taurine transporter (TAUT) mRNA levels reduced by 47% and 64% ( P < .05), respectively, and cysteine sulfinate decarboxylase (CSD) mRNA reduced slightly, but not significantly. Time-dependent taurine uptakes reduced in the 10, 20, and 30 mmol/L glucose-treated cells, and time-dependent taurine release reduced in the 30 mmol/L glucose-treated cells. The V max of taurine transport decreased by 18%, 30%, and 35% ( P < .05) in the 10, 20, and 30 mmol/L glucose-treated cells, respectively, while K m of taurine transport remained unchanged. When PKC inhibitor, Chelerythrine, combined with 30 mmol/L glucose was treated with the cells, the lowered taurine content, taurine uptake, taurine release, and V max of taurine transport caused by 30 mmol/L glucose were eliminated. These results demonstrate that high glucose considerably and specifically decreases intracellular taurine content, taurine transport activity, and TAUT mRNA, possibly through PKC-mediated transcriptional and posttranslational pathways.

A specific taurine recognition site in the rabbit brain is responsible for taurine effects on thermoregulation.

(1) Taurine and GABA are recognized as endogenous cryogens. In a previous study, some structural analogues of taurine, namely 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (TAG), 2-aminoethylarsonic (AEA), 2-hydroxyethanesulfonic (ISE) and (+/-)cis-2-aminocyclohexane sulfonic acids (CAHS) have been shown to displace [(3)H]taurine binding from rabbit brain synaptic membrane preparations, without interacting either with GABA-ergic systems, nor with taurine uptake mechanism, thus behaving like direct taurinergic agents. (2) To answer the question whether the role of taurine as an endogenous cryogen depends on the activation of GABA receptors or that of specific taurine receptor(s), taurine or the above structural analogues were injected intracerebroventricularly in conscious, restrained rabbits singularly or in combination and their effects on rectal (RT)- and ear-skin temperature and gross motor behavior (GMB) were monitored. (3) Taurine (1.2 x 10(-6)-4.8 x 10(-5) mol) induced a dose-related hypothermia, vasodilation at ear vascular bed and inhibition of GMB. CAHS, at the highest dose tested (4.8 x 10(-5) mol) induced a taurine-like effect either on RT or GMB. On the contrary ISE, injected at the same doses of taurine, induced a dose-related hyperthermia, vasoconstriction and excitation of GMB. AEA and TAG caused a dose-related hyperthermia, but at doses higher than 1.2 x 10(-7) mol caused death within 24 h after treatment. (4) CAHS (4.8 x 10(-5) mol) antagonized the hyperthermic effect induced by TAG (1.2 x 10(-6) mol), AEA (1.2 x 10(-8) mol) or ISE (4.8 x 10(-5) mol). (5) In conclusion, these findings may indicate the existence of a recognition site specific for taurine, responsible for its effects on thermoregulation.

Interactions of taurine and structurally related analogues with the GABAergic system and taurine binding sites of rabbit brain.

1. The aim of this study was to find taurinergic compounds that do not interact with brain GABA ergic systems. 2. Washed synaptic membranes (SM) from whole rabbit brain were able to bind [(3)H]muscimol. Saturation experiments of the binding of [(3)H]GABA to GABA(B) receptors showed that SM possess two binding components; twice Triton X-100-treated SM contained 0.048 mmol endogenous taurine/kg protein and bound [(3)H]taurine in a saturable manner (K(d)=249.0+/-6.3 nM and B(max)=3.4+/-1.0 pmol mg(-1) prot). 3. Among the 19 structural analogues of taurine, 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (TAG), 2-aminoethylarsonic (AEA), 2-hydroxyethanesulfonic (ISE) and (+/-)cis-2-aminocyclohexane sulfonic acids (CAHS) displaced [(3)H]taurine binding (K(i)=0.13, 0.13, 13.5 and 4.0 micro M, respectively). These analogues did not interact with GABA(A) and GABA(B) receptors and did not affect taurine- and GABA-uptake systems and GABA-transaminase activity. 4. 3-Aminopropanesulfonic acid (OMO), beta-alanine, pyridine-3-sulfonic acid, N,N,N-trimethyltaurine (TMT), 2-(guanidino)ethanesulfonic acid (GES), ethanolamine-O-sulphate, N,N-dimethyltaurine (DMT), taurine and (+/-)piperidine-3-sulfonic acid (PSA) inhibited [(3)H]muscimol binding to GABA(A) receptors with different affinities (K(i)=0.013, 7.9, 24.6, 47.5, 52.0, 91.0, 47.5, 118.1 and 166.3 micro M, respectively). Taurine, 2-aminoethylphosphonic acid, DMT, TMT and OMO inhibited the binding of [(3)H]GABA to GABA(B) receptors with K(i)'s in the micro M range (0.8, 3.5, 4.4, 11.3 and 5.0, respectively). GES inhibited taurine uptake (IC(50)=3.72 micro M) and PSA GABA transaminase activity (IC(50)=103.0 micro M). 5. In conclusion, AEA, TAG, ISE and CAHS fulfill the criteria for taurinergic agents.

Taurine transporter in primary cultured neonatal rat heart cells: a comparison between cardiac myocytes and nonmyocytes

In the present study, we examined the characteristics of the taurine transporter and the intracellular taurine content in cultured neonatal heart cells. Primary cultures of cardiac myocytes and cardiac fibroblasts (nonmyocytes) were prepared from 1-day-old Wistar rats. The parameters examined were: (a) intracellular taurine content by the HPLC method, (b) the expression levels of taurine transporter mRNA and protein using northern and western blot analysis, and (c) transporter activity determined by the uptake of 3 H -labeled taurine. The taurine content of myocytes was significantly higher (3-fold) than that of nonmyocytes. Taurine transporter mRNA was strongly expressed in both myocytes and nonmyocytes, whereas the magnitude [normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene expression] of the transporter mRNA expressed in myocytes was lower than that in nonmyocytes. The expression level of transporter protein in myocytes was also lower than that of nonmyocytes. Uptake of radiolabeled taurine into monolayer cultures of heart cells was stimulated markedly by the presence of Na + in the medium, whereas this uptake was almost abolished in the absence of Na +. The Na +/taurine stoichiometry was 2:1 for both myocytes and nonmyocytes. Kinetic analysis showed that a single saturable system was involved in taurine uptake into both cell types. In myocytes, the apparent K m and V max values for the transporter were 20.7±0.5 μM and 1.07±0.01 nmol/10 6 cells/30 min, respectively. Similarly, those of nonmyocytes were 20.3±0.7 μM and 0.42±0.01 nmol/10 6 cells/30 min. These findings indicated that both myocytes and nonmyocytes expressed an identical taurine transporter with a Michaelis–Menten constant of 20–21 μM and that a higher taurine content in myocytes may be associated with a higher V max.

Plasma taurine concentrations increase after enteral glutamine supplementation in trauma patients and stressed rats

Taurine is a unique amino acid with antioxidant and osmolytic properties. Glutamine serves as the preferred fuel for the gut, liver, and immune cells and as a precursor for antioxidants. Trauma patients have low glutamine concentrations. We investigated the effect of glutamine-enriched enteral nutrition on plasma taurine concentrations in patients with severe trauma (injury severity score >20). Additionally, plasma taurine concentrations and organ fluxes were studied in a stressed rat model. Twenty-nine patients with multiple trauma received glutamine-enriched nutrition and 31 patients received isocaloric, isonitrogenous control solution for 5 d. Plasma taurine and glutamine concentrations were measured. Male Wistar rats (250-300 g) received a glutamine-enriched diet (12%, by wt) or a control solution for 2 wk. Plasma taurine concentrations were measured. Taurine fluxes and fractional extraction rates in the liver, kidneys, and gut were assessed with a radioactive microsphere technique. Both patient groups had low taurine concentrations on day 1. From day 3 onward, the glutamine-fed patients had significantly higher taurine concentrations. Rats fed a glutamine-enriched diet had significantly higher plasma taurine concentrations than did the controls. A high taurine uptake was found in the liver, kidneys, and gut of the glutamine-fed rats. Fractional extraction rates were not significantly different between the rat groups. Glutamine enrichment increases plasma taurine in trauma patients and in stressed rats. Because of increased availability, organ fluxes showed a higher taurine uptake in the liver, kidneys, and gut. The reduction in morbidity with glutamine enrichment could be explained in part by increased taurine availability.

Taurine uptake and release by the pancreatic beta-cells: taurine transport in beta-cells.

The β-amino acid taurine is abundantly present in its free form in various mammalian cells and tissues1, including the islet of Langerhans2. Although the exact physiological role of taurine in the pancreas is not understood, a number of studies suggest a possible role of taurine in glucose metabolism. Taurine has been shown to attenuate streptozotocin-induced diabetes in animals3, to increase the stimulatory effects of conventional secretagogues in cultured fetal β-cells4, and to protect against β-cells injury by NO and IL-1 beta5. Most interestingly, hyposmotic challenge that induces taurine release in many cells1 has been shown to increase secretion of insulin6,7.KeywordsHill EquationTaurine TransporterTaurine ReleaseTaurine UptakeNipecotic AcidThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Insulin-stimulated taurine uptake in the rat retina.

The sulfur amino acid taurine is found in millimolar concentrations in excitable tissues, especially those which generate oxidants. Taurine is involved in a variety of biological phenomena such as osmoregulation, antioxidation, detoxification, neuronal modulation, cell proliferation and cell viability1,2. Taurine is the most abundant amino acid in the retina of all species studied. In the rat retina, taurine accounts for more than 50% of the total free “amino acid pool3–5.The intraretinal distribution of taurine is heterogeneous being largely concentrated in photoreceptors. A high taurine concentration is essential for maintenance of the structural and functional integrity of retina6.

Hypotonic-induced transport pathways in Xenopus laevis erythrocytes: taurine fluxes

Taurine fluxes in Xenopus laevis red cells were studied in vitro in media of different tonicities. Both influx and efflux increased 3–10 times reversibly when dilution of the medium exceeded 30%. The absolute values of uptake ranged between 5 and 30 μmol/l cells·h at extracellular taurine concentration of 1 mmol/l, but is poorly selective as almost the same uptake was measured for choline and sucrose. Q 10 of 2.77 and an activation energy of 71.90±7.37 kJ/mol were calculated for the uptake process. Taurine uptake was reduced 50% in the absence of Cl −, whereas the alkali cations (Na +, K +, Li + and Rb +) supported it similarly. Taurine uptake was greatly increased in Ca 2+-free solution, and was inhibited by alkaline pH. The inhibitor of anion exchange protein, 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid (IC 50=25 μM) and the Cl − channel blockers 5-nitro-2-(3-phenylpropylamino) benzoic acid and [(dihydro-indenyl) oxy] alkanoic acid (IC 50<20 μM) inhibited taurine uptake effectively. Isoproterenol did not affect taurine uptake in isotonic, nor in hypotonic solution. The uptake was reduced slowly to near the original, control level within 15–30 min in hypotonic solutions, indicating deactivation of the hypotonic-induced taurine pathway.

Regulation of taurine transport at the blood-brain barrier by tumor necrosis factor-alpha, taurine and hypertonicity.

Taurine is the abundant sulfur-containing beta-amino acid in brain where it exerts a neuroprotective effect. Although it is known that the blood-brain barrier (BBB) mediates taurine transport, the regulation of taurine transport have not been clarified yet. A conditionally immortalized rat brain capillary endothelial cells (TR-BBB13), an in vitro model of the BBB, exhibited [3H]taurine uptake, which was dependent on both Na+ and Cl-, and inhibited by beta-alanine. Taurine transporter (TAUT) mRNA was detected in TR-BBB13 cells, and TAUT protein was also expressed at 70 kDa. TR-BBB13 cells exposed to 20 ng/mL TNF-alpha and under hypertonic conditions showed a 1.7-fold and 3.2-fold increase in [3H]taurine uptake, respectively. In contrast, lipopolysaccharide and diethyl maleate did not significantly affect taurine uptake. The taurine uptake was reduced by pre-treatment with excess taurine (50 mm). The mRNA level of the TAUT in TNF-alpha and following hypertonic treatment was greater than that in control cells, whereas that under excess taurine conditions was lower than in controls. Therefore, taurine transport activity at the BBB appears to be regulated at the transcriptional level by cell damage, osmolality and taurine in the brain.

Mechanism of the reduced elimination clearance of benzylpenicillin from cerebrospinal fluid in rats with intracisternal administration of lipopolysaccharide.

The mechanism responsible for the reduced clearance of benzylpenicillin (BPC) from the cerebrospinal fluid (CSF) was investigated in rats that received an intracisternal administration of lipopolysaccharide (LPS). BPC was intraventricularly injected and its elimination from the CSF studied. During the inflammation created by the LPS administration to the cisterna magna, the clearance of BPC and taurine from the CSF was significantly reduced but reverted to the control level when N-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor, was intracisternally administered. The in vitro uptake of BPC and taurine was significantly reduced in the choroid plexus (CP, the blood-CSF barrier) of rats with experimental inflammation and in control CP that had been pretreated with sodium nitroprusside (SNP, an NO donor). Interestingly, the clearance and CP uptake of formycin B, a substrate for a nucleoside transporter, were not affected by the experimental inflammation or by pretreatement with SNP. These observations suggest that the BPC transporter, and probably other transport systems as well, is functionally sensitive to NO in the blood-CSF barrier. Therefore, functional impairment of BPC transport in the CP by NO may be partly responsible for the increase in BPC concentration in the CSF during inflammation such as that caused by meningitis.

Effect of dietary sulfur amino acids on the taurine content of rat tissues.

The effect of dietary sulfur amino acids on the taurine content of rat blood and tissues was investigated. Three types of diet were prepared for this study: a low-taurine diet (LTD), normal taurine diet (NTD; LTD + 0.5% Met), and high-taurine diet (HTD; LTD + 0.5% Met + 3% taurine). These diets had no differing effect on the growth of the rats. The concentration of taurine in the blood from the HTD- and NTD-fed rats was respectively 1200% and 200% more than that from LTD-. In such rat tissues as the liver, the taurine content was significantly affected by dietary sulfur amino acids, resulting in a higher content with HTD and lower content with LTD. However, little or no effect on taurine content was apparent in the heart or eye. The activity for taurine uptake by the small intestine was not affected by dietary sulfur amino acids. The expression level of taurine transporter mRNA was altered only in the kidney under these dietary conditions: a higher expression level with LTD and lower expression level with HTD.

Manganese Causes Differential Regulation of Glutamate Transporter (GLAST) Taurine Transporter and Metallothionein in Cultured Rat Astrocytes

Neurotoxicity due to excessive brain manganese (Mn) can occur due to environmental (air pollution, soil, water) and/or metabolic aberrations (decreased biliary excretion). Manganese is associated with oxidative stress, as well as alterations in neurotransmitter metabolism with concurrent neurobehavioral deficits. Based on the few existing studies that have examined brain regional [Mn], it is likely that in pathological conditions it can reach 100–500 μM. Amino acid (e.g. aspartate, glutamate, taurine), as well as divalent metal (e.g. zinc, manganese) concentrations are regulated by astrocytes in the brain. Recently, it has been reported that cultured rat primary astrocytes exposed to Mn displayed decreased glutamate uptake, thereby, increasing the excitotoxic potential of glutamate. Since the neurotoxic mechanism(s) Mn employs in terms of glutamate metabolism is unknown, a primary goal of this study was to link altered glutamate uptake in Mn exposed astrocytes to alterations in glutamate transporter message. Further, we wanted to examine the gene expression of metallothionein (MT) and taurine transporter (tau-T) as markers of Mn exposure. Glutamate uptake was decreased by nearly 40% in accordance with a 48% decrease in glutamate/aspartate transporter (GLAST) mRNA. Taurine uptake was unaffected by Mn exposure even though tau-T mRNA increased by 123%. MT mRNA decreased in these Mn exposed astrocytes possibly due to altered metal metabolism, although this was not examined. These data show that glutamate and taurine transport in Mn exposed astrocytes are temporally different.

Long-lasting enhancement of corticostriatal neurotransmission by taurine.

Taurine occurs at high concentrations in the forebrain and its distribution varies with (patho)physiological conditions; however, its role in neural function is poorly understood. We have now characterized its effects on corticostriatal synaptic transmission. Bath application of taurine (10 mm) to slices obtained from mice and rats exerted a biphasic action on corticostriatal field potentials. The fast and reversible inhibition by taurine was accompanied by a depolarization and conductance increase in medium spiny neurons and was sensitive to gamma-aminobutyric acid (GABA)A and glycine receptor (GlyR) antagonists. A long-lasting enhancement (LLETAU) of field potentials was recorded after taurine withdrawal. The LLETAU was not prevented by N-methyl-d-aspartate (NMDA)- or by GABAA receptor-antagonists, but was sensitive to the GlyR-antagonist strychnine and blocked by the competitive taurine uptake inhibitor guanidinoethylsulphonate (GES, 1 mm). GES at 10 mm evoked an enhancement of field potentials similar to LLETAU. LLETAU depended on protein kinase C activation as it was blocked by chelerythrine, but was unaffected by trifluoperazine, and thus independent of calmodulin. LLETAU was significantly smaller in juvenile than in mature rodents. Activation of GlyRs and the specific taurine transporter by taurine evoke a long-lasting enhancement of corticostriatal transmission.