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PubMed1981

The activity of rat pineal and brain tyrosine hydroxylase during the daily cycle of light and darkness as determined by the modified 14CO2 assay method.

A previous published assay method for tyrosine hydroxylase by the evolution of 14CO2 was modified to a two-step procedure to allow reliable measurement of large numbers of samples containing low tyrosine hydroxylase activity. The reliability of the method was examined in detail. Properties of rat brain and pineal tyrosine hydroxylase solubilized with 0.2% Triton X-100 were as follows. The apparent Km values of the brain enzyme for L-tyrosine with 1 mM-(6-DL)-5,6,7,8-tetrahydro-L-erythro-biopterin (BPH4) as cofactor and for BPH4 with 62 microM-L-tyrosine as substrate were approximately 25 microM and 85 microM, respectively. The Km's for L-tyrosine with 1 mM-(6-DL)-5,6,7,8-tetrahydro-6-methylpterin (6MPH4) as cofactor and for 6MPH4 with 210 microM-L-tyrosine as substrate were 68 microM and 270 microM, respectively. The marked substrate inhibition by high concentrations of L-tyrosine was observed only when BPH4 was used as cofactor. High concentrations of BPH4 inhibited the reaction slightly. The kinetic properties of tyrosine hydroxylase in the pineal extract were similar to those of the brain enzyme, except that a Lineweaver-Burk plot of reciprocal velocity versus the reciprocal concentration of BPH4 with 62 microM-L-tyrosine as substrate deviated downward at a BPH4 concentration of about 100 microM. Analyses of the plot indicated that the peculiar kinetic property may represent either the reaction occurring at two independent sites or with two forms (6L- and 6D-isomers) of the tetrahydrobiopterin cofactor, with apparent Km for BPH4 of 23 microM and 1025 microM, respectively, or the negatively cooperative ligand binding with a Hill coefficient of 0.72. Based on the results obtained as reported above the standard assay conditions of tyrosine hydroxylase in tissue extracts were established. Using the assay method and conditions, the absence of the daily rhythmicity of tyrosine hydroxylase in rat pineal glands and three discrete brain areas was demonstrated. The findings, especially on pineal tyrosine hydroxylase, are discussed in relation to the daily change of noradrenaline turnover.

Animals↗
PubMed2006

Tomato aromatic amino acid decarboxylases participate in synthesis of the flavor volatiles 2-phenylethanol and 2-phenylacetaldehyde.

An important phenylalanine-derived volatile compound produced by plants is 2-phenylethanol. It is a major contributor to flavor in many foods, including fresh fruits, such as tomato, and an insect-attracting scent in roses and many other flowers. Despite the centrality of 2-phenylethanol to flavor and fragrance, the plant genes responsible for its synthesis have not been identified. Here, we describe a biosynthetic pathway for 2-phenylethanol and other phenylalanine-derived volatiles in tomato fruits and a small family of decarboxylases (LeAADC1A, LeAADC1B, and LeAADC2) that can mediate that pathway's first step. These enzymes each catalyze conversion of phenylalanine to phenethylamine and tyrosine to tyramine. Although tyrosine is the preferred substrate in vitro, phenylalanine levels in tomato fruits far exceed those of tyrosine, indicating that phenylalanine is a physiological substrate. Consistent with this view, overexpression of either LeAADC1A or LeAADC2 in transgenic tomato plants resulted in fruits with up to 10-fold increased emissions of the products of the pathway, including 2-phenylacetaldehyde, 2-phenylethanol, and 1-nitro-2-phenylethane. Further, antisense reduction of LeAADC2 significantly reduced emissions of these volatiles. Besides establishing a biosynthetic route, these results show that it is possible to change phenylalanine-based flavor and aroma volatiles in plants by manipulating expression of a single gene.

Acetaldehyde↗
PubMed1990

D1 receptors function to inhibit the activation of tuberoinfundibular dopamine neurons.

The effects of the D1 dopamine agonists SKF 38393 and CY 208-243 on the activity of tyrosine hydroxylase within tuberoinfundibular dopamine neurons were studied by measuring the accumulation of dihydroxyphenylalanine (DOPA) in the median eminence in vivo after inhibition of DOPA decarboxylase. SKF 38393 (5-20 mg/kg) and CY 208-243 (5-20 mg/kg) alone did not alter the accumulation of DOPA in the median eminence of male rats. However, the haloperidol-, reserpine- and neurotensin-induced increases in DOPA formation in the median eminence were antagonized dose-dependently by SKF 38393 (5-20 mg/kg i.p.) and/or CY 208-243 (5-20 mg/kg i.p.). Treatment of rats with SCH 23390 (0.5 mg/kg i.p.), a selective D1 antagonist, or loxapine (5 mg/kg i.p.), a dopamine antagonist with high affinity for D1 receptors, prevented the inhibitory effect of CY 208-243 on the haloperidol-induced activation of tyrosine hydroxylase in the median eminence. SKF 38393 did not inhibit the basal activity or the haloperidol-induced increase in activity of tyrosine hydroxylase in the striatum or nucleus accumbens. It is concluded that D1 receptor activation results in little or no effect on the basal rate of dopamine synthesis within tuberoinfundibular dopamine neurons, but under conditions in which the activity of tyrosine hydroxylase is increased D1 receptor stimulation results in a marked inhibition of the rate of dopamine synthesis within these neurons.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1985

Hepatic cyclic AMP generation and ornithine decarboxylase induction by glucagon and beta adrenergic agonists.

The relationship of hepatic ornithine decarboxylase (ODC) activity to cyclic AMP levels and nutritional status was studied in the pre-weanling rat. Previous studies demonstrated that 2 hr without food causes a loss of hepatic ODC induction after glucagon or catecholamine injection. Isoproterenol or glucagon administration produced increased hepatic cyclic AMP and tyrosine aminotransferase activity which were not prevented by nutritional deprivation. Blockade of hepatic beta 2 receptors by the selective antagonist ICI 118,551 prevented increased cAMP levels and ODC activity after isoproterenol administration. Blockade of beta 1 receptors by atenolol did not prevent increased cAMP levels or ODC induction by isoproterenol although it did block activation of cardiac ODC. The phosphodiesterase inhibitor RO20-1724 increased hepatic cAMP levels as well as ODC and TAT activities, although the increase in ODC activity was attenuated by nutritional deprivation. RO20-1724 also potentiated the induction of hepatic ODC after glucagon or isoproterenol administration. Administration of 8-bromo cAMP elevated hepatic ODC activity regardless of nutritional status but also elevated serum levels of growth hormone and corticosterone. Hepatic ODC induction by glucagon or beta 2 agonists can be dissociated from changes in cAMP levels during nutritional deprivation.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1992

Effects of l-stepholidine on tyrosine hydroxylase activity in rat corpus striatum.

l-Stepholidine (SPD) 2.5 and haloperidol (Hal) 1.0 mg.kg-1 ip increased rat striatal L-3,4-dihydroxyphenylalanine (DOPA) and 3,4-dihydroxyphenylacetic acid (DOPAC) accumulation induced by NSD 1015 (50 mg.kg-1, ip), a decarboxylase inhibitor. SPD (2.5 mg.kg-1, ip) did not alter but apomorphine (2.0 mg.kg-1, ip) decreased the dopamine (DA) content elevated by gamma-butyrolactone (GBL, 750 mg.kg-1, ip) in the rat striatum. Ip injection of either SPD 5.0 or Hal 2.5 mg.kg-1 after NSD 1015 50 mg.kg-1 or NSD 1015 plus GBL 750 mg.kg-1 also augmented tyrosine hydroxylase (TH) activity in the rat striatum. These results suggest that SPD produces an antagonistic effect on presynaptic DA receptors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Serotonergic and dopaminergic influence of the duration of embryogenesis and intracapsular locomotion of Lymnaea stagnalis L.

The role of the dopaminergic and serotonergic system was studied during the embryonic development of the pond snail Lymnaea stagnalis, with special attention to the effect of dopamine and serotonin as well as their agonists and antagonists on the rotation of the veliger larvae, and to the effect of precursors and inhibitors of the synthetizing enzymes on the duration of the embryonic life. Serotonin, D-lysergic acid diethylamide and N,N-dimethyltryptamine increased at a concentration of 1 microM the rotation by 50%, 90% and 87% respectively, and among them D-Lysergic acid diethylamide was found to be the most potent agonist. Other serotonergic agonists and antagonists enhanced the frequency of the rotation (from 165% to 355%) at higher threshold concentrations in the following rank order: methysergid > tryptamine > 2,5-dimethoxy-4-iodoamphetamine > 5-carboxyamidotryptamine > bromo-lysergic acid diethylamide > 7-methyltryptamine. Application of 1-(2-methoxyphenyl) piperazine decreased the rotation by 76%. The reuptake inhibitor desipramine completely blocked the rotation and killed the embryos. Dopaminergic agonists accelerated the rotation by 62% to 233%, and their effect was ranged as follows: dopamine > apomorphine > m-tyramine approximately equal to p-tyramine. Chlorpromazine at 100 microM concentration killed the embryos. At a concentration of 100 microg/ml, tyrosine, the precursor of DA, slowed down the embryonic development by increasing the duration of the embryonic life from 8 to 10 days. Decarboxylase inhibitors, alpha-methyl-3,4-dihydroxyphenyl-alanine (25 microg/ml) and m-hydroxybenzylhydrazin (5 microg/ml), killed 50% of the embryos, meanwhile the rest hatched ten days later, compared to the control animals. The development was partially blocked by the serotonin precusor L-tryptophane (50 microg/ml). Trytophan hydroxylase blocker, p-chlorphenylalanine (50 microg/ml) resulted in a distortion of the body pattern of the embryos, and prevented the hatching of most (95%) of the animals.

Amphetamines↗
PubMed1978

Antagonism of morphine-induced central stimulation in mice by small doses of catecholamine-receptor agonists.

The morphine (75 mg/kg i.p.) induced stimulation of motor activity in mice was significantly suppressed by small doses of central catecholamine (CA) receptor agonists, apomorphine (0.2 mg/kg) and clonidine (0.05 mg/kg). In the same dose, and at the same time interval as the behavioural stimulation was obtained, morphine did not significantly affect the in vivo rate of tyrosine hydroxylation in two dopamine (DA)-rich mouse brain regions, the corpus striatum and in the limbic system, or in the noradrenaline (NA)-rich, but DA-poor hemispheres, measured as the Dopa-accumulation during 30 min after inhibition of aromatic amino-acid decarboxylase by 3-hydroxybenzylhydrazine (NSD 1015) 150 mg/kg. The apomorphine induced reduction in Dopa accumulation in the DA-rich brain regions was not significantly affected by morphine. The disappearance rate of brain NA after inhibition of tyrosine hydroxylase by alpha-methyltyrosine methylester (250 mg/kg), the utilization of NA, was accelerated by morphine, whereas that of DA was not affected. Clonidine (0.05 mg/kg) retarded selectively brain NA utilization, and also suppressed the morphine-induced increase in NA utilization. In conclusion, morphine's stimulation of motor activity in mice, an effect which previously has been found to be correlated with its dependence producing action, could be inhibited by apomorphine or clonidine in small doses which inhibit brain DA- and NA-neurons, respectively. Thus, we have now shown the psychomtor stimulation by two euphoriant and dependence-producing drugs, ethanol and morphine, to be suppressed by CA "autoreceptor" activation.

Animals↗
PubMed1993

Role of tyrosine kinase activity in signal transduction by the insulin-like growth factor-I (IGF-I) receptor. Characterization of kinase-deficient IGF-I receptors and the action of an IGF-I-mimetic antibody (alpha IR-3).

The insulin-like growth factor-I (IGF-I) receptor is a member of a large family of transmembrane signal transducing molecules. The defining characteristic of this class of receptors is the intrinsic tyrosine kinase activity of the cytoplasmic domain. While it has been demonstrated that this tyrosine kinase activity is necessary for the action of a number of transmembrane tyrosine kinase receptors, no evidence of this type has been adduced to date with respect to the signaling requirement of the IGF-I receptor. We have now shown that stably transfected NIH-3T3 cell lines overexpressing human IGF-I receptors display increased responses to IGF-I and an IGF-I-mimetic antibody, alpha IR-3, in terms of short, intermediate, and long term actions initiated by activation of the IGF-I receptor. These include receptor autophosphorylation, activation of phosphatidylinositol-3-kinase and 2-deoxyglucose uptake, induction of ornithine decarboxylase gene expression, and stimulation of thymidine incorporation. In short term responses, the kinetics seen with alpha IR-3 were slower than those seen with IGF-I. These effects were severely decreased in clones expressing human IGF-I receptors in which the lysine residue in the ATP-binding site of the tyrosine kinase domain had been mutated to alanine or arginine. This was true for both IGF-I and alpha IR-3. These results indicate that, for all parameters tested, the tyrosine kinase activity of the IGF-I receptor is necessary for activation of the IGF-I-stimulated signal transduction cascade. Additionally, the effects of alpha IR-3 also require tyrosine kinase activity.

3T3 Cells↗
PubMed2004

Sub-chronic exposure to toluene at 40 ppm alters the monoamine biosynthesis rate in discrete brain areas.

Effects of long-term exposure to a sub-toxic concentration of toluene (40 ppm, 104 h per week, 16 weeks) have been studied on monoamine biosynthesis rate in rat. The activities of the rate limiting enzymes in catecholamine and 5-hydroxytryptamine biosynthesis tyrosine and tryptophan hydroxylase, respectively, were estimated in vivo by measuring the accumulation of l-dihydroxyphenylalanine and 5-hydroxytryptophan after pharmacological blockade of l-aromatic acid decarboxylases by NSD-1015 (100 mg kg(-1) ip). The sub-chronic exposure to toluene led to a significant and gender dependent alteration in both catecholamine and 5-hydroxytryptamine biosynthesis rate in brainstem catecholaminergic cell groups and hypothalamus. In females exposed to toluene, changes in tryptophan hydroxylation were found in rostral subset of A2C2 (+41%) and in A1C1 (+41%) while a decrease in A5 (-44%) and an increase in A2C2 (+28%) were found in tyrosine hydroxylation. In males, an increase in tryptophane hydroxylation was observed in rostral subset of A2C2 (+35%) while a decrease was observed in ventro-median hypothalamus (-17%). These results suggest that toluene exposure to a dose generally recognized as sub-toxic (40 ppm, no observed adverse effect level) leads to adverse effects on monoaminergic systems. Therefore, the neurotoxicity of toluene should be carefully re-evaluated taking into account not only the exposure level but also the duration.

5-Hydroxytryptophan↗
PubMed1984

Ontogenesis of dopaminergic neurons in the post-natal rabbit retina: pre- and post-synaptic elements.

The post-natal development of several aspects of the dopaminergic system in the rabbit have been examined. Dopamine (DA) itself was barely detectable from soon after birth up to about 7 days of age. Thereafter, dramatic increases in the retinal content of DA and also of the two major enzymes involved in its biosynthesis were observed, approaching adult values by about 16 days. These changes occur when functional synapses are being formed as judged by electrophysiological and anatomical studies. On the other hand, the post-synaptic target of these neurons, DA-stimulated adenylate cyclase could be easily detected at 3 days of age and did not appear to undergo any dramatic changes in activity during development. The affinity of haloperidol for this receptor did, however, appear to decrease with age suggesting that the receptor is 'born' in a supersensitive state but attains 'normal' properties after the onset of DA neurotransmission. Depletion of DA stores during these early stages by irreversible inhibition of biosynthesis in vivo did not appear to halt the development of tyrosine hydroxylase or have any irrevocable effects on DA neurons. This suggests that the continued presence of neurotransmitter is not necessary for the developmental process to continue that the commitment of particular neurons to become dopaminergic may be made earlier than 5-6 days post-natally.

3,4-Dihydroxyphenylacetic Acid↗