Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We reported previously that, following phosphorylation by cyclic AMP-dependent protein kinase, tyrosine hydroxylase in rat corpus striatal extracts is inactivated in a time-dependent and apparently irreversible fashion. Removal of low molecular weight substances from these extracts by gel filtration attenuates this inactivation. We tried to determine the identity of endogenous metabolites that promote inactivation of tyrosine hydroxylase under our experimental conditions. In the present study, we report that the reducing co-substrate tetrahydrobiopterin and its analogues promoted this irreversible inactivation. The concentration that produced a 50% loss of activity (at 20 min) of the phosphorylated enzyme was 0.7 microM and that for the unphosphorylated enzyme was 420 microM. Using enzyme purified from a rat pheochromocytoma, we found that tyrosine, alpha-methyl-p-tyrosine, and a 3-iodotyrosine protected the phosphorylated enzyme against the inactivation produced by tetrahydrobiopterin. Catecholamines (dopamine, norepinephrine, epinephrine, and some of their analogues) also nullified inactivation. In contrast, the product of the reaction, dihydroxyphenylalanine, failed to attenuate the inactivation process. We performed several studies to ascertain the mechanism of inhibition by tetrahydrobiopterin. We considered the possibility that it formed reactive free radicals that produced inhibition. Free radical scavengers, however, failed to block the inhibition produced by tetrahydrobiopterin. Superoxide dismutase, catalase, and peroxidase also failed to protect tyrosine hydroxylase against inactivation. Moreover, when the experiments were performed under anaerobic conditions, the inactivation process was unaffected. These results suggest that reactive oxygenated species were not required for inactivation by tetrahydrobiopterin.
Mol Pharmacol 1990 Oct
PMID:Inactivation of tyrosine hydroxylase by pterin substrates following phosphorylation by cyclic AMP-dependent protein kinase. 197 41

Unilateral naris cauterization in rats results in occlusion of the affected naris and blockade of odorant access to ipsilateral olfactory receptor cells in the olfactory epithelium. These receptor cells project exclusively to the olfactory bulb (OB) and appear to regulate expression of the dopaminergic phenotype in a population of OB juxtaglomerular neurons. Unilateral odor deprivation results in a loss of normal stimulatory input to the OB and a marked and specific decrease in ipsilateral OB tyrosine hydroxylase (TH) expression. The expression of co-localized aromatic L-amino acid decarboxylase (AADC) is not similarly affected. We have used this procedure in neonatal rats to examine the effect of stimulus deprivation on OB TH and AADC mRNA levels. Both Northern blot and in situ hybridization analyses revealed a pronounced decrease in ipsilateral as compared to contralateral OB TH mRNA levels 40 days after naris closure. In contrast, the levels of OB AADC mRNA were unaltered by naris closure. By in situ hybridization histochemistry, both TH and AADC mRNAs were localized to OB juxtaglomerular neurons. Odor deprivation was associated with an apparent region-specific reduction in TH mRNA within the ipsilateral OB glomerular layer. By densitometric analysis, the loss of TH-specific message was quantitatively consistent with the decrease in TH activity, suggesting that the observed plasticity of OB dopaminergic neurons following functional deafferentation can be attributed to a selective, transneuronally-mediated down regulation of TH gene transcription.
Brain Res Mol Brain Res 1990 Oct
PMID:Decrease in tyrosine hydroxylase, but not aromatic L-amino acid decarboxylase, messenger RNA in rat olfactory bulb following neonatal, unilateral odor deprivation. 198 Jan 39

The exposure of the cephalic end of rats to repeated doses of X-irradiation (150 rad) immediately after birth induces a long-term increase in the noradrenaline (NA) content of cerebellum (CE) (+ 37.8%), and a decrease in cerebellar weight (65.2% of controls), which results in an increased NA concentration (+ 109%). This increase in the neurotransmitter level is accompanied by a dystonic syndrome and histological abnormalities: Purkinje cells (the target cells for NA afferents to CE) fail to arrange in a characteristic monolayer, and their primary dendritic tree appears randomly oriented. The injection of reserpine 0.9 and 1.2 mg/kg ip to adult rats for 18 h depletes cerebellar NA content in both controls (15.7 +/- 4 ng/CE and 2.8 +/- 1.5 ng/CE, respectively) and X-irradiated rats (17.1 +/- 1 ng/CE and 8.3 +/- 2 ng/CE, respectively). The activity of tyrosine hydroxylase (TH) in CE of adult rats, measured by an in vitro assay, is significantly increased in neonatally X-irradiated animals when compared to age-matched controls (16.4 +/- 1.4 vs 6.32 +/- 0.6 nmol CO2/h/mg prot., p less than 0.01). As observed for NA levels, a net increase in TH activity induced by the ionizing radiation is also measured: 308.9 +/- 23.8 vs 408.2 +/- 21.5 nmol CO2/h/CE, p less than 0.01 (controls and X-treated, respectively). These results suggest that X-irradiation at birth may induce an abnormal sprouting of noradrenergic afferents to CE. The possibility that these changes represent a response of the NA system to the dystonic syndrome is discussed.
Mol Chem Neuropathol
PMID:Increased activity of tyrosine hydroxylase in the cerebellum of the X-irradiated dystonic rat. 198 78

1. Earlier reports from this and other laboratories have indicated that wide variations exist in estimates of the concentrations of norepinephrine in the brain and heart of the snail Helix aspersa. This is a report on investigations of norepinephrine concentrations in Helix aspersa tissues using high-performance liquid chromatography with electrochemical detection. In addition, the effects of treatment with some amino acid precursors or enzyme inhibitors on the concentrations of norepinephrine, dopamine, 5-hydroxytryptamine, and some of their metabolites were investigated. 2. The levels of norepinephrine in the brain were low (46 ng/g) in comparison to dopamine (2.1) micrograms/g) and 5-hydroxytryptamine (2.6 micrograms/g). Epinephrine was not observed in either snail heart of snail nervous tissue. 3. Administration of L-3,4-dihydroxyphenylalanine resulted in elevated snail brain dopamine, while 3,4-dihydroxyphenylserine treatment increased norepinephrine. Treatment with blockers of tyrosine hydroxylase and aromatic-L-amino acid decarboxylase reduced dopamine concentrations without affecting 5-hydroxytryptamine. 4. The dopamine metabolite 3,4-dihydroxyphenylacetic acid was observed only after administration of L-3,4-dihydroxyphenylalanine or dopamine and then only in very small amounts. At no time was the dopamine metabolite homovanillic acid or the 5-hydroxytryptamine metabolite 5-hydroxyindoleacetic acid observed in brain, heart, or whole-body extracts of the snail. 5. Incubation of nervous tissue with either dopamine or 5-hydroxytryptamine resulted in the production of electrochemically active metabolites which were identified by oxidation characteristics and cochromatography with synthesized standards as the gamma-glutamyl conjugates of the amines. Treatment of snails with 5-hydroxytryptamine or dopamine also resulted in the production of gamma-glutamyl conjugates. 6. The present experiments show that great care must be exercised when measuring monoamines and their metabolites in gastropod tissues by high-performance liquid chromatography with electrochemical detection.
Cell Mol Neurobiol 1990 Jun
PMID:High-performance liquid chromatographic analysis of monoamines and some of their gamma-glutamyl conjugates produced by the brain and other tissues of Helix aspersa (Gastropoda). 211 17

The enzymatic activity of tyrosine hydroxylase (EC 1.14.16.2) increases in rat pheochromocytoma PC18 cells exposed to either elevated levels of cyclic AMP or glucocorticoids. The cyclic AMP-mediated increase in activity is elicited by cyclic AMP analogs or by compounds which activate adenylate cyclase or inhibit phosphodiesterase. The glucocorticoid-mediated increase is elicited only by glucocorticoid steroid hormones; nonglucocorticoid steroid hormones have no effect on tyrosine hydroxylase. In PC18 cells exposed simultaneously to both cyclic AMP-elevating agents and glucocorticoids, the increase in tyrosine hydroxylase activity is greater than that observed in cells treated with optimal concentrations of either inducing agent alone. Immunochemical titration experiments demonstrate that the increases in tyrosine hydroxylase activity observed in cells treated with the cyclic AMP analog, 8-bromocyclic AMP, and/or the synthetic glucocorticoid, dexamethasone, are due to increases in enzyme protein. Time course studies show that in cells treated with either 8-bromocyclic AMP or dexamethasone, the enzyme level increases slowly to a level 5-7-fold greater than that observed in untreated cells after 4 days of treatment. In cells treated with both of these inducing agents simultaneously, the enzyme level increases to a level 10-12-fold greater than that observed in control cells after 4 days of treatment. This additive increase in activity in cells treated with both inducing agents is observed at all time points. The rates of synthesis and degradation of tyrosine hydroxylase have also been measured in PC18 cells, using an antiserum to tyrosine hydroxylase to rapidly isolate radiolabeled enzyme from cells that have been incubated in the presence of [3H]leucine. The apparent half-life of tyrosine hydroxylase in the PC18 cells is approximately 30 hr. In PC18 cells incubated in the presence of radiolabeled leucine for 60 min, 0.2-0.3% of the total soluble protein synthesized is identified as tyrosine hydroxylase. In cells treated with either 8-bromocyclic AMP or dexamethasone for 24 hr, there is a 6-8-fold increase in the rate of synthesis of the enzyme. In cells treated with both inducing agents simultaneously, there is a 10-12-fold increase in the rate of synthesis; thus, the additive increase in enzyme level observed in cells treated with both inducing agents is paralleled by an additive increase in the rate of synthesis of the enzyme in these cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1986 Nov
PMID:Induction of tyrosine hydroxylase by cyclic AMP and glucocorticoids in a rat pheochromocytoma cell line: effect of the inducing agents alone or in combination on the enzyme levels and rate of synthesis of tyrosine hydroxylase. 243 Jan 69

In the rat, decreasing transsynaptic activity through adrenal denervation, nicotinic receptor blockade, or explanation is associated with an increase in preproenkephalin mRNA, enkephalin prohormone and peptide. In contrast, catecholamine pathways remain unchanged under similar conditions. Since it is not known whether changes in messenger RNA result from stabilization or increased synthesis, we exploited transcription 'run-on' assays to measure the rate of transmitter gene read out. Tyrosine hydroxylase message (TH-mRNA) was found to be the most abundantly produced transcript in the unmanipulated control rat adrenal medulla. TH-mRNA was produced in excess of twice the rate of transcription of the structural gene beta-actin. In contrast, preproenkephalin transcription occurred at a much lower rate (60% of the actin gene and only 25% of tyrosine hydroxylase gene transcription). All transcripts were inhibited by the polymerase II inhibitor, alpha-amanitin. After two days in explant culture, the rate of enkephalin transcription increased approximately 2-fold (to the same level as actin transcription); while tyrosine hydroxylase transcriptional activity fell to 30% of actin level. To analyze cellular mechanisms, explants were depolarized with potassium chloride. Enkephalin gene transcription was observed to be 2.5-fold less when grown under depolarizing conditions (50 mM KCl) than in control explants. On the other hand, tyrosine hydroxylase gene read-out was unchanged, similar to results obtained when TH catalytic activity was measured. These data indicate that membrane depolarization can selectively regulate expression of a transmitter gene product and are consistent with a proposed transsynaptic regulatory mechanism controlling biosynthesis of adrenal opiate peptides.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1989 Jan
PMID:Transcriptional control of adrenal catecholamine and opiate peptide transmitter genes. 256 22

Regulation of preprosomatostatin mRNA and tyrosine hydroxylase mRNA were examined in sympathetic neurons of the rat superior cervical ganglion (SCG). Surgical denervation of the adult SCG increased ganglion levels of preprosomatostatin (SS) mRNA more than 11-fold, and levels of the mRNA remained elevated 14 days after surgery. By contrast, denervation decreased levels of tyrosine hydroxylase (TH) mRNA. Potassium- or veratridine-induced membrane depolarization of cultured neonatal sympathetic neurons decreased levels of SS mRNA but elevated levels of TH mRNA. Sodium channel blockade with tetrodotoxin prevented the effects of veratridine on SS and TH mRNAs. In toto these observations suggest that transsynaptic nerve impulse activity and sympathetic neuron membrane depolarization decrease SS synthesis but increase TH synthesis at the mRNA level. Thus nerve impulse activity may alter the relative levels of different transmitters co-expressed in the same neuronal population by inhibiting levels of some species of mRNA while simultaneously stimulating levels of others.
Brain Res Mol Brain Res 1989 Jan
PMID:Differences in the effects of membrane depolarization on levels of preprosomatostatin mRNA and tyrosine hydroxylase mRNA in rat sympathetic neurons in vivo and in culture. 256 23

Long-term effects of lesions were analyzed in terms of gene expression. Nine months after unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (s. nigra), the remaining dopaminergic (DAergic) neurons (tyrosine hydroxylase (TH) cells determined by immunocytochemistry (ICC] on the lesioned side were atrophic with smaller nucleoli. By in situ hybridization, the DAergic neurons on the lesioned side had a 50% smaller TH-mRNA concentration than on the contralateral non-lesioned side. However, beta-tubulin mRNA concentration in DAergic neurons was unaffected by the lesion. The lesions did not alter TH-mRNA concentration in the contralateral non-lesioned side by comparison with unoperated controls. We propose that chronic lesions have long-term effects on gene expression because of damage sustained during compensatory hyperactivity after the lesion, or because of decreased trophic support from other neurons.
Brain Res Mol Brain Res 1989 May
PMID:Chronic lesions differentially decrease tyrosine hydroxylase messenger RNA in dopaminergic neurons of the substantia nigra. 256 83

The distribution of nerve fibers showing neuropeptide Y-like immunoreactivity (NPY-LI) was compared with the distribution of the sympathetic nerve fibers in all parts of the conduction system and adjacent atrial and ventricular tissue of the bovine heart. Tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) served as markers for the sympathetic nerve fibers. NPY-LI was detected in most of the sympathetic nerve fibers that were present in nerve fascicles and that were associated with conduction cells and arterial walls in all regions examined. This phenomenon was more apparent when staining for NPY was compared with staining for DBH than with staining for TH. It was also found that some nerve varicosities exhibiting NPY-LI in association with arterial walls and local ganglia did not show DBH-LI. Furthermore, some of the ganglionic cells located in the regions of the conduction system showed NPY-LI but not DBH- or TH-LI. The observations are discussed in relation to what is known of the subcellular localization of NPY, TH and DBH. It is furthermore concluded that an NPY-like peptide is present in the sympathetic innervation of all parts of the conduction system and ordinary myocardial tissue, but that this peptide is also present in nerve fibers in the heart that do not represent sympathetic fibers. The observations raise important questions for further research aimed at determining the effects of NPY in relation to the function of the conduction system and in relation to the functions of not only sympathetic but also non-sympathetic nerve fibers in the heart.
J Mol Cell Cardiol 1989 Mar
PMID:Neuropeptide Y-like immunoreactivity in relation to the distribution of sympathetic nerve fibers in the heart conduction system. 256 93

Human SMS-KCNR cells differentiated in response to either retinoic acid or phorbol esters; differentiated cells extended numerous, complex neurites and showed reduced proliferation. Tyrosine hydroxylase (TH) immunoreactivity was measured in this cell line following treatment with retinoic acid (1-10 microM), 12-O-tetradecanoyl-phorbol-13-acetate (TPA; 16-160 nM), or combinations of these agents. After 21 days of treatment with either TPA or retinoic acid (RA), TH immunoreactivity was measured in this using densitometric scans of Western blots, was doubled relative to untreated or serum-deprived SMS-KCNR cultures. Increases in TH immunoreactivity could be detected after 6 days of treatment. Treatment with RA for 3 days followed by phorbol esters for an additional 3 days resulted in a 3-fold increase in TH immunoreactivity at day 6; reversing the order of drug treatment did not have this effect. Treatment of cultures with the divalent cationophore A23187 caused treated cells to retract neurites; expression of TH immunoreactivity was decreased relative to drug-treated and control cultures. These results suggest that retinoic acid treatment may 'prime' SMS-KCNR cells for the subsequent effects of phorbol esters, and indicate that the patterns of biochemical differentiation induced by TPA or RA are different.
Brain Res Mol Brain Res 1989 Jun
PMID:Changes in expression of tyrosine hydroxylase immunoreactivity in human SMS-KCNR neuroblastoma following retinoic acid or phorbol ester-induced differentiation. 256 72


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