Taurine and Its Chloramine: Modulators of Immunity

Taurine is a semiessential amino acid that is not incorporated into proteins. In mammalian tissues, taurine is ubiquitous and is the most abundant free amino acid in the heart, retina, skeletal muscle, and leukocytes. Taurine reaches up to 50 mM concentration in leukocytes. Taurine has been shown to be tissue-protective in many models of oxidant-induced injury. One possibility is that taurine reacts with HOCl, produced by the myeloperoxidase (MPO) pathway, to produce the more stable but less toxic taurine chloramine (Tau-Cl). However, data from several laboratories demonstrate that Tau-Cl is a powerful regulator of the immune system. Specifically, Tau-Cl has been shown to downregulate the production of proinflammatory mediators in both rodent and human leukocytes. Recent molecular studies on the function of taurine provide evidence that taurine is a constituent of biological macromolecules. Specifically, two novel taurine-containing modified uridines have been found in both human and bovine mitrochondria. In studies on mechanism of action, Tau-Cl inhibits the activation of NFkappaB, a potent signal transducer for inflammatory cytokines, by oxidation of IkappaB alpha at methionine45. Taurine transporter knockout mice show reduced taurine, reduced fertility, and loss of vision resulting from severe retinal degeneration, which was found to be due to apoptosis. Apoptosis induced by amino chloramines is a current and important finding because oxidants derived from leukocytes play a key role in killing pathogens. The fundamental importance of taurine in adaptive and acquired immunity will be revealed using genetic manipulation.     

Effect of taurine on ischemia–reperfusion injury

Taurine is an abundant β-amino acid that regulates several events that dramatically influence the development of ischemia–reperfusion injury. One of these events is the extrusion of taurine and Na⁺ from the cell via the taurine/Na⁺ symport. The loss of Na⁺ during the ischemia–reperfusion insult limits the amount of available Na⁺ for Na⁺/Ca²⁺ exchange, an important process in the development of Ca²⁺ overload and the activation of the mitochondrial permeability transition, a key process in ischemia–reperfusion mediated cell death. Taurine also prevents excessive generation of reactive oxygen species by the respiratory chain, an event that also limits the activation of the MPT. Because taurine is an osmoregulator, changes in taurine concentration trigger “osmotic preconditioning,” a process that activates an Akt-dependent cytoprotective signaling pathway that inhibits MPT pore formation. These effects of taurine have clinical implications, as experimental evidence reveals potential promise of taurine therapy in preventing cardiac damage during bypass surgery, heart transplantation and myocardial infarction. Moreover, severe loss of taurine from the heart during an ischemia–reperfusion insult may increase the risk of ventricular remodeling and development of heart failure.     

The effect of taurine on the ion transport system in mitochondria

The effect of taurine on the ATP-dependent mitochondrial swelling that characterizes the activity of mitochondrial ATP-dependent K⁺ channel and the formation of Ca²⁺-dependent pores, different in sensitivity to cyclosporin A, has been studied in rat liver mitochondria. It has been shown that taurine in micromolar concentrations (0.5–125 μM) stimulates the energy-dependent swelling of mitochondria. Taurine in physiological concentrations (0.5–20 mM) has no effect on the ATP-dependent swelling and the formation of cyclosporin A-insensitive Pal/Ca²⁺-activated pore in mitochondria. Taurine in these concentrations increased the rate of cyclosporin A-sensitive swelling of mitochondria induced by Ca²⁺ and P_i and reduced the Ca²⁺ capacity of mitochondria. The different effects of physiological taurine concentrations on the ATP-dependent transport of K⁺ and Ca²⁺ ions in mitochondrial membranes as compared with cell membranes are discussed.     

Taurine: A therapeutic agent in experimental kidney disease

Summary Taurine is an abundant free amino acid in the plasma and cytosol. The kidney plays a pivotal role in maintaining taurine balance. Immunohistochemical studies reveal a unique localization pattern of the amino acid along the nephron. Taurine acts as an antioxidant in a variety ofin vitro andin vivo systems. It prevents lipid peroxidation of glomerular mesangial cells and renal tubular epithelial cells exposed to high glucose or hypoxic culture conditions. Dietary taurine supplementation ameliorates experimental renal disease including models of refractory nephrotic syndrome and diabetic nephropathy. The beneficial effects of taurine are mediated by its antioxidant action. It does not attenuate ischemic or nephrotoxic acute renal failure or chronic renal failure due to sub-total ablation of kidney mass. Additional work is required to fully explain the scope and mechanism of action of taurine as a renoprotective agent in experimental kidney disease. Clinical trials are warranted to determine the usefulness of this amino acid as an adjunctive treatment of progressive glomerular disease and diabetic nephropathy.     

Taurine and neural cell damage

Summary. The inhibitory amino acid taurine is an osmoregulator and neuromodulator, also exerting neuroprotective actions in neural tissue. We review now the involvement of taurine in neuron-damaging conditions, including hypoxia, hypoglycemia, ischemia, oxidative stress, and the presence of free radicals, metabolic poisons and an excess of ammonia. The brain concentration of taurine is increased in several models of ischemic injury in vivo. Cell-damaging conditions which perturb the oxidative metabolism needed for active transport across cell membranes generally reduce taurine uptake in vitro, immature brain tissue being more tolerant to the lack of oxygen. In ischemia nonsaturable diffusion increases considerably. Both basal and K⁺-stimulated release of taurine in the hippocampus in vitro is markedly enhanced under cell-damaging conditions, ischemia, free radicals and metabolic poisons being the most potent. Hypoxia, hypoglycemia, ischemia, free radicals and oxidative stress also increase the initial basal release of taurine in cerebellar granule neurons, while the release is only moderately enhanced in hypoxia and ischemia in cerebral cortical astrocytes. The taurine release induced by ischemia is for the most part Ca²⁺-independent, a Ca²⁺-dependent mechanism being discernible only in hippocampal slices from developing mice. Moreover, a considerable portion of hippocampal taurine release in ischemia is mediated by the reversal of Na⁺-dependent transporters. The enhanced release in adults may comprise a swelling-induced component through Cl⁻ channels, which is not discernible in developing mice. Excitotoxic concentrations of glutamate also potentiate taurine release in mouse hippocampal slices. The ability of ionotropic glutamate receptor agonists to evoke taurine release varies under different cell-damaging conditions, the N-methyl-D-aspartate-evoked release being clearly receptor-mediated in ischemia. Neurotoxic ammonia has been shown to provoke taurine release from different brain preparations, indicating that the ammonia-induced release may modify neuronal excitability in hyperammonic conditions. Taurine released simultaneously with an excess of excitatory amino acids in the hippocampus under ischemic and other neuron-damaging conditions may constitute an important protective mechanism against excitotoxicity, counteracting the harmful effects which lead to neuronal death. The release of taurine may prevent excitation from reaching neurotoxic levels. Received January 25, 2000/Accepted January 31, 2000     

Interaction between the actions of taurine and angiotensin II

Summary. The amino acid, taurine, is an important nutrient found in very high concentration in excitable tissue. Cellular depletion of taurine has been linked to developmental defects, retinal damage, immundeficiency, impaired cellular growth and the development of a cardiomyopathy. These findings have encouraged the use of taurine in infant formula, nutritional supplements and energy promoting drinks. Nonetheless, the use of taurine as a drug to treat specific diseases has been limited. One disease that responds favorably to taurine therapy is congestive heart failure. In this review, we discuss three mechanisms that might underlie the beneficial effect of taurine in heart failure. First, taurine promotes natriuresis and diuresis, presumably through its osmoregulatory activity in the kidney, its modulation of atrial natriuretic factor secretion and its putative regulation of vasopressin release. However, it remains to be determined whether taurine treatment promotes salt and water excretion in humans with heart failure. Second, taurine mediates a modest positive inotropic effect by regulating [Na⁺]_i and Na⁺/Ca²⁺ exchanger flux. Although this effect of taurine has not been examined in human tissue, it is significant that it bypasses the major calcium transport defects found in the failing human heart. Third, taurine attenuates the actions of angiotensin II on Ca²⁺ transport, protein synthesis and angiotensin II signaling. Through this mechanism taurine would be expected to minimize many of the adverse actions of angiotensin II, including the induction of cardiac hypertrophy, volume overload and myocardial remodeling. Since the ACE inhibitors are the mainstay in the treatment of congestive heart failure, this action of taurine is probably very important. Received November 10, 1998, Accepted May 19, 1999     

Taurine Stimulation of Isolated Hamster Brain Na+, K+-ATPase: Activation Kinetics and Chemical Specificity

Epileptic foci are associated with locally reduced taurine (2-aminoethanesulfonic acid) concentration and Na⁺, K⁺-ATPase (EC 3.6.1.3) specific activity. Topically applied and intraperitoneally administered taurine can prevent the development and/or spread of foci in many animal models. Taurine has been implicated as a possible cytosolic modulator of monovalent ion distribution, cytosolic “free” calcium activity, and neuronal excitability. Taurine may act in part by modulating Na⁺, K⁺-ATPase activity of neuronal and glial cells. We characterized the requirements for in vitro modulation of Na⁺, K⁺-ATPase by taurine. Normal whole brain homogenate Na⁺, K⁺-ATPase activity is 5.1 ± 0.4 (4) μmol P_i± h^?1± mg^?1 Lowry protein. Partial purification of the plasma membrane fraction to remove cytosolic proteins and extrinsic proteins and to uncouple cholinergic receptors yields a membrane-bound Na⁺, K⁺-ATPase activity of 204.6 ± 5.8 (4) mol P_i± h^?1± mg^?1 Lowry protein. Taurine activates the Na⁺, K⁺-ATPase at all levels of purification. The concentration dependence of activation follows normal saturation kinetics (K_1/2= 39 mM taurine, activation maximum =+87%). The activation exhibits chemical specificity among the taurine analogues and metabolites: taurine = isethionic acid > hypotaurine > no activation =β-alanine = methionine = choline = leucine. Taurine can act as an endogenous activator/modulator of Na⁺, K⁺-ATPase. Its action is mediated by a membrane-bound protein.     

Effect of taurine on calcium binding to microsomes isolated from rat cerebral cortex

Effects of taurine on Ca⁺⁺ binding to microsomes isolated from rat cerebral cortex were investigated in a medium containing various concentrations of KCl and/or NaCl. Calcium binding to microsomes was inhibited in a dose-dependent fashion by taurine in the incubation medium containing 5 mM KCl and 115 mM NaCl, while there was no inhibition in the medium containing 115 mM KCl and 5 mM NaCl. Taurine also decreased Ca⁺⁺ binding in the medium containing 70 mM KCl without NaCl. A similar tendency toward inhibition of the Ca⁺⁺ binding was observed in the medium with 5 mM or 120 mM KCl without NaCl. Taurine did not influence the Ca⁺⁺ binding in the medium containing different concentrations of NaCl without KCl, or in the medium from which KCl and NaCl were omitted. Isethionate, glycine, γ-aminobutyric acid, β-alanine and L-leucine did not significantly alter the Ca⁺⁺ binding to microsomes in the medium containing 70 mM KCl without NaCl. Thus it would appear that taurine may modulate the binding of calcium to microsomes in conditions which resemble the state of depolarization, while it is inactive in the normal resting state. This effect is apparently specific to taurine amongst a series of putative “inhibitory” amino acids.     

Effects of taurine on calcium binding and accumulation in rabbit hippocampal and cortical synaptosomes

The effect of taurine on Ca²⁺ binding and uptake was studied with rabbit brain cortical and hippocampal synaptosomes. Taurine (25 mM) increased by 25% the high affinity ⁴⁵Ca²⁺ binding in the cortical fraction and by 55% in hippocampal synaptosomes but had no effect on low affinity Ca²⁺ binding. Taurine decreased significantly the fluorescence of the chlorotetracycline-hydrophobic Ca²⁺ chelate probe in both synaptosomal fractions which suggests a shift of bound Ca²⁺ from the hydrophobic to the hydrophilic part of the membranes. The uptake of ⁴⁵Ca²⁺ by rabbit brain synaptosomes, when measured in control and 65 mK K⁺-containing media, was not influenced by taurine. However, taurine inhibited significantly the ⁴⁵Ca²⁺ uptake in synaptosomes incubated in media containing moderately increased K⁺ concentrations (14 and 20 mM K⁺). The effects of taurine are discussed in conjunction with its stabilizing effect on excitable membranes.     

Cell volume regulation in fish heart ventricles with special reference to taurine

A review of the cell volume regulation mechanism in heart ventricles of teleosts reveal that the mechanism is not only restricted to euryhaline species in a changing salinity regime but also is manifested in fresh-water fish. Taurine is the dominating amino acid and the main cellular osmo-effector in teleost hearts (accounting for 40-50% of the osmolality change). During hypo-osmotic regulation, cellular taurine is reduced by an efflux from the cells, whereas intracellular synthesis of taurine most probably accompanies hyper-osmotic regulation. Vertebrate hearts seem to have a high concentration of taurine and it may in general in vertebrate hearts also play a pivotal role in cellular osmoregulatory function.     

Protective effects of taurine against oxidative stress in the heart of MsrA knockout mice

Taurine has been shown to have potent anti‐oxidant properties under various pathophysiological conditions. We reported previously a cellular dysfunction and mitochondrial damage in cardiac myocytes of methionine sulfoxide reductase A (MsrA) gene knockout mice (MsrA^?/?). In the present study, we have explored the protective effects of taurine against oxidative stress in the heart of MsrA^?/? mice with or without taurine treatment. Cardiac cell contractility and Ca²⁺ dynamics were measured using cell‐based assays and in vivo cardiac function was monitored using high‐resolution echocardiography in the tested animals. Our data have shown that MsrA^?/? mice exhibited a progressive cardiac dysfunction with a significant decrease of ejection fraction (EF) and fraction shortening (FS) at age of 8 months compared to the wild type controls at the same age. However, the dysfunction was corrected in MsrA^?/? mice treated with taurine supplement in the diet for 5 months. We further investigated the cellular mechanism underlying the protective effect of taurine in the heart. Our data indicated that cardiac myocytes from MsrA^?/? mice treated with taurine exhibited an improved cell contraction and could tolerate oxidative stress better. Furthermore, taurine treatment reduced significantly the protein oxidation levels in mitochondria of MsrA^?/? hearts, suggesting an anti‐oxidant effect of taurine in cardiac mitochondria. Our study demonstrates that long‐term treatment of taurine as a diet supplement is beneficial to a heart that is vulnerable to environmental oxidative stresses. J. Cell. Biochem. 113: 3559–3566, 2012. © 2012 Wiley Periodicals, Inc.     

牛磺酸与心脏及其疾病的研究进展

<正> 牛磺酸(Taurine,Tau.2-氨基乙磺酸)为体内一种β-氨基酸,属于非蛋白质氨基酸。主要分布在兴奋性较高的组织如神经系统、肌肉组织、视网膜及血小板中。近年来研究认为牛磺酸不仅参与合成胆汁酸、调节渗透压、阻断神经冲动的功能,还有抗氧化及维持膜稳定性等方面作用。自从     

Taurine stimulation of isolated hamster brain Na+,K+-ATPase: activation kinetics and chemical specificity

Epileptic foci are associated with locally reduced taurine (2-aminoethanesulfonic acid) concentration and Na+,K+-ATPase (EC 3.6.1.3) specific activity. Topically applied and intraperitoneally administered taurine can prevent the development and/or spread of foci in many animal models. Taurine has been implicated as a possible cytosolic modulator of monovalent ion distribution, cytosolic "free" calcium activity, and neuronal excitability. Taurine may act in part by modulating Na+,K+-ATPase activity of neuronal and glial cells. We characterized the requirements for in vitro modulation of Na+,K+-ATPase by taurine. Normal whole brain homogenate Na+,K+-ATPase activity is 5.1 +/- 0.4 (4) mumol Pi X h-1 X mg-1 Lowry protein. Partial purification of the plasma membrane fraction to remove cytosolic proteins and extrinsic proteins and to uncouple cholinergic receptors yields a membrane-bound Na+,K+-ATPase activity of 204.6 +/- 5.8 (4) mol Pi X h-1 X mg-1 Lowry protein. Taurine activates the Na+,K+-ATPase at all levels of purification. The concentration dependence of activation follows normal saturation kinetics (K1/2 = 39 mM taurine, activation maximum = +87%). The activation exhibits chemical specificity among the taurine analogues and metabolites: taurine = isethionic acid greater than hypotaurine greater than no activation = beta-alanine = methionine = choline = leucine. Taurine can act as an endogenous activator/modulator of Na+,K+-ATPase. Its action is mediated by a membrane-bound protein.     

Effects of sulfur containing amino acids on iron and nitric oxide stimulated catecholamine oxidation

Summary.  Taurine is a free amino acid found in high concentrations in tissues containing catecholamines. The ability of taurine and its metabolic precursors to inhibit or stimulate catecholamine oxidation and subsequent quinone formation was examined. Ferric chloride was used as the catalyzing agent to stimulate L-dopa or norepinephrine oxidation and NO donors were also examined for their actions to stimulate quinone formation. Taurine attenuated iron-stimulated quinone formation from catecholamines suggesting that it may function as an endogenous antioxidant. Several other sulfur-containing amino acids (homocysteic acid, cysteine sulfinic acid and SAM) were found to inhibit catecholamine oxidation. Among other amino acids tested, homocysteine had biphasic effects; attenuating L-dopa oxidation catalyzed by ferric chloride and potentiating norepinephrine's oxidation catalyzed by both ferric chloride and sodium nitroprusside (SNP). Homotaurine and homocysteine (1 or 10 mM) greatly stimulated SNP-induced norepinephrine oxidation. Homotaurine potentiated quinone formation in the presence of ferric iron and this effect was attenuated by desferroxamine. In order to exclude a possible NO/iron interaction in SNP's oxidizing action, SIN-1 chloride, a specific NO-donor, was tested as an oxidizing agent. The failure of desferroxamine or taurine to attenuate SIN-1 oxidation of norepinephrine suggests that peroxynitrite-mediated oxidation was likely the dominant mechanism. Our results show that endogenous sulfur containing amino acids, like taurine, could serve a protective role to reduce cellular damage associated with both NO and metal-stimulated catecholamine oxidation. Received August 20, 2001 Accepted October 10, 2001     

Taurine-induced attenuation of MPP+ neurotoxicity in vitro: a possible role for the GABA(A) subclass of GABA receptors

Taurine is a sulphur-containing beta-amino acid found in high (millimolar) concentrations in excitable tissues such as brain and heart. Its suggested roles include osmoregulator, thermoregulator, neuromodulator, and potential neurotransmitter. This amino acid has also been shown to be released in large concentrations during ischaemia and excitotoxin-induced neuronal damage. Here we report a protective effect of taurine against MPP(+)-induced neurotoxicity in coronal slices from rat brain. Significant protective effects were observed at taurine concentrations of 20 and 1 mM, suggesting a potential role for taurine in cases of neuronal insult. Studies with the synthetic taurine analogues taurine phosphonate, guanidinoethane sulphonate, and trimethyltaurine suggested the observed effect to be mediated via an extracellular mechanism. The use of GABA receptor ligands muscimol and bicuculline indicated the effect to be mediated through activation of GABA(A) receptors.     

Role of taurine in osmoregulation in brain cells: Mechanisms and functional implications

Summary All cells including neurons and glial cells are able to keep their volume within a very limited range. The volume regulatory mechanism involves changes in the concentration of osmolytes of which taurine appears to be of particular importance in brain cells. Swelling in brain cells may occur as a result of depolarization or small fluctuations in osmolarity. In isolated brain cells these conditions will always lead to a release of taurine, the time course of which is superimposable on that of the volume regulatory decrease which follows the initial cell swelling. The mechanism responsible for taurine release associated with swelling has not been fully elucidated but a large body of evidence seems to exclude participation of the taurme high affinity carrier. Using a number of inhibitors of anion exchangers it has been demonstrated that both volume regulation and taurine release in brain cells are inhibited by these drugs, implicating an anion channel in the process. It has be controversial issue as to whether or not taurine release is Ca++ dependent. Recent evidence appears to suggest that the release process is not associated with Ca⁺⁺ or Ca⁺⁺ channels. It is, however, quite possible that the swelling process may involve the Ca⁺⁺ calmodulin system or other second messengers. Taurine also contributes to volume regulation after shrinkage of brain cells, in this case by increasing its intracellular concentration. This change is accomplished byan upregulation of the Na+/taurine cotransporter, together with reduced passive fluxes and increased endogenous synthesis.     

Cardiac and skeletal muscle abnormality in taurine transporter-knockout mice

Taurine, a sulfur-containing β-amino acid, is highly contained in heart and skeletal muscle. Taurine has a variety of biological actions, such as ion movement, calcium handling and cytoprotection in the cardiac and skeletal muscles. Meanwhile, taurine deficiency leads various pathologies, including dilated cardiomyopathy, in cat and fox. However, the essential role of taurine depletion on pathogenesis has not been fully clarified. To address the physiological role of taurine in mammalian tissues, taurine transporter-(TauT-) knockout models were recently generated. TauTKO mice exhibited loss of body weight, abnormal cardiac function and the reduced exercise capacity with tissue taurine depletion. In this chapter, we summarize pathological profile and histological feature of heart and skeletal muscle in TauTKO mice.     

Cardiac functions and taurine's actions at different extracellular calcium concentrations in forced swimming stress-loaded rats

Modulation of the sinus rate and contractile force by taurine at different extracellular Ca²⁺ concentrations ([Ca²⁺]_o) was examined using rat right atria loaded with forced swimming stress. Serum concentration of corticosterone profoundly increased in stress-loaded rats as compared with native rats. The taurine level in serum also increased in stress-loaded rats, but was not changed in the different heart tissues and aorta. Heat-shock protein (HSP72) was detectable in cardiac muscles and in the lumen of cardiac blood vessels of stress-loaded rats using a monoclonal antibody. Increasing [Ca²⁺]_o (from 0.9 to 3.6 mM) enhanced the sinus rate and contractile force in a [Ca²⁺]_o-dependent fashion in native rats, but not in stress-loaded rats. Taurine (1–20 mM) caused a negative chronotropic and inotropic effect in a concentration-dependent manner. At 1.8 mM [Ca²⁺]_o, the negative chronotropic effect of taurine (10–20 mM) was attenuated in stress-loaded rats as compared with native rats. These results indicate that swimming stress causes a release of taurine into the serum and reduces the sensitivity to [Ca²⁺]_o. Taurine administration might, in part, exhibit the protective actions on acute stress-induced responses.     

Taurine and its Trophic Effects in the Retina Lucimey Lima

The sulphur amino acid taurine possesses variable functions during development and regeneration of the central nervous system. The retina synthesize and uptake taurine, which is the amino acid present in the highest concentration in this tissue. Deficiency of taurine alters the structure and the function of the cerebral and cerebelar cortex, as well as the retina. Taurine increases outgrowth of postcrush goldfish retina in culture, partially by elevating calcium influx, and also by the modulation of protein phosphorylation. Its concentration increases in the retina after the lesion of the optic nerve, and the intraocular injection of it, between the crush and the explantation, stimulates the outgrowth of neurites. Taken together, although there are a great number of unresolved questions on the mechanisms of action of this amino acid as atrophic substance, the results support the role of taurine during regeneration of the optic nerve.     

Taurine-diabetes interaction: from involvement to protection

Taurine is a sulfur amino acid (2-amino ethane sulfonic acid) and has been claimed for a number of beneficial actions ranging from anti-epilepsy to anti-hypertension. Taurine in diabetes has an age old story; taurine is involved in the development and protection of insulin apparatus. Taurine and insulin both have mutual stimulating actions with hypoglycemic properties. On the clinical front, taurine supplementation has an acceptable beneficial effect in platelet aggregation and, to name few more, in neuropathy, cardiomyopathy, and nephropathy to retinopathy. Recent studies have provided a role for taurine in fetal development and in blocking the transfer of diabetes from diabetic mother to offspring. A number of mechanisms for the actions of taurine have been advocated, from osmoregulation to anti-oxidation. Though sulfonylurea and recently introduced thiazolidinediones are effective, however they are not free from complications, thus there is a need to design new therapeutics. As taurine is also a sulfonyl derivative, it will be of great interest to develop taurine analogues as an alternative therapy. Considering the great involvement of taurine in diabetes, this review may provide a holistic view of taurine in diabetes and in its prevention in this century.