Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two clonal cell lines (the pheochromocytoma clone PC-12 and the neuroblastoma clone N1E-115) were used to compare direct and indirect drug effects on tyrosine hydroxylase and dopamine turnover. Both clones contain the cofactor of tyrosine hydroxylase, tetrahydrobiopterin, in sufficient concentrations. 2,4-Diamino-6-hydroxy-pyrimidine (DAO-Pyr), an inhibitor of GTP cyclohydrolase, which is the rate-limiting enzyme in tetrahydrobiopterin biosynthesis, lowers DOPA production indicating that cofactor supply is a limiting factor for catecholamine synthesis. DOPA synthesis in the PC-12 cells can be stimulated by incubation with the natural cofactor tetrahydrobiopterin, but also by its possible precursors sepiapterin and dihydrobiopterin or the analogs methyl-tetrahydropterin and dihydropterin. The regulating enzyme for DOPA synthesis, tyrosine hydroxylase, can be inhibited by certain drugs either directly or indirectly by increasing dopamine concentrations in the cytoplasm after release from its vesicular stores. Using the neuroblastoma clone N1E-115 which lacks DOPA decarboxylase and thus contains only low levels of dopamine the site of action of certain drugs could be determined. Drugs affecting the tyrosine hydroxylase directly (alpha-methyl-para-tyrosine, apomorphine) decreased DOPA production in both clones, while drugs acting via interference with the vesicular stores (reserpine, amphetamine, nigericin) were effective only in the PC-12 cells. After total depletion of dopamine by nigericin at high concentrations or long-term incubation with 3-hydroxybenzyl-hydrazine (NSD 1015), DOPA production increased in the PC-12 cells indicating a usually occurring regulation of tyrosine hydroxylase by cytoplasmic dopamine. Dopamine concentration in the cytoplasm was calculated to be in the range of 1 X 10(-6) mol/l.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evaluation of neurotropic drug actions on tyrosine hydroxylase activity and dopamine metabolism in clonal cell lines. 285 29

A significant amount of 5,6,7,8-tetrahydrobiopterin (BH4), an essential cofactor of tyrosine hydroxylase, and the activity of GTP cyclohydrolase (GTP cycl), the first and rate-limiting enzyme in BH4 biosynthesis, were found in rat salivary glands, in which adrenergic transmitters are localized, from day 4 through 56 after birth. About 90 ng of BH4 per g wet weight were determined in the glands (submandibular and sublingual) of adult rats. The levels of them which were maintained from 2 weeks after birth up to the adult stage correlated with a previous finding in the maintenance of catecholamine concentration during the same stage in rat salivary glands.
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PMID:Development of tetrahydrobiopterin and GTP cyclohydrolase in salivary glands of rats. 286 34

The hydroxylase cofactor, tetrahydrobiopterin, and its biosynthetic system are localized in dopaminergic nerve terminals in the striatum. This conclusion is based on the nearly equivalent loss of tyrosine hydroxylase and tetrahydrobiopterin and its initial biosynthetic enzyme, guanosine triphosphate cyclohydrolase, after injection of 6-hydroxydopamine into the substantia nigra. The role of the hydroxylase cofactor in the regulation of dopamine synthesis is reassessed.
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PMID:Tetrahydrobiopterin in striatum: localization in dopamine nerve terminals and role in catecholamine synthesis. 611 45

We examined by immunohistochemistry the effect of salt loading on the expression of tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), and GTP cyclohydrolase I (GCH) in Purkinje cells of the mouse cerebellum. In control mice, only a few Purkinje cells were positive for TH or AADC. No Purkinje cells were stained for GCH. Drinking 2% sodium chloride for 2 weeks resulted in an increase in the number of TH- or AADC-positive Purkinje cells in the caudal vermis, paraflocculus and flocculus of the cerebellum. In contrast, no Purkinje cells were immunoreactive to GCH or L-DOPA after the salt loading. The present findings suggest that the salt loading differentially affects the expression of TH, AADC and GCH in Purkinje cells of the mouse cerebellum.
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PMID:Enhanced expression of tyrosine hydroxylase and aromatic L-amino acid decarboxylase in cerebellar Purkinje cells of mouse after hyperosmotic stimuli. 747

The past 18 months have seen significant advances in our understanding of dopa(dihydroxyphenylalanine)-responsive dystonia. Clinical investigations have broadened the spectrum of disease with particular attention manifestations in infancy. Pathophysiological investigations have revealed features that distinguish dopa-responsive dystonia from childhood-onset parkinsonism. A pathological study has confirmed the 'developmental' nature of the disease. Finally, mutations causing the autosomal dominant form of dopa-responsive dystonia have been identified in the gene coding for GTP cyclohydrolase I. Mutations in tyrosine hydroxylase have been identified in two brothers and put forward as evidence of an autosomal recessive form of the disease.
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PMID:Dopa-responsive dystonia. 758 48

GTP cyclohydrolase I activity in mononuclear blood cells from patients with juvenile parkinsonism (JP) was found to be normal compared to healthy controls. The normal activity in JP contrasts strongly with the decreased activity of 2-20% normal levels in hereditary progressive dystonia with marked diurnal fluctuation (HPD) or dopa responsive dystonia (DRD). The result indicates that the decreased dopamine level in the basal ganglia in JP is not due to decreased activity of GTP cyclohydrolase I, the enzyme for the biosynthesis of the tetrahydrobiopterin cofactor of tyrosine hydroxylase (TH), and the enzyme activity in mononuclear blood cells could be a reliable method for differential diagnosis between JP and HPD/DRD.
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PMID:GTP cyclohydrolase I activity in mononuclear blood cells in juvenile parkinsonism. 764 24

Development of the dopamine (DA) neuron phenotype was monitored in cultures of embryonic rat mesencephalon (MES) and hypothalamus (HYP) maintained for 1 to 21 days in vitro (DIV) in the absence of glial support cells. Cell counts following immunohistochemistry for tyrosine hydroxylase (TH) demonstrated that the number of DA neurons declined by 85% in MES cultures yet increased 5-fold in cultures of HYP, so that by 21 DIV equal numbers of DA neurons were present in these culture systems. After 21 DIV MES DA neurons exhibited a multipolar morphology, with numerous branching processes. HYP DA neurons were primarily fusiform in shape with fewer processes and process branch points. Double-label immunohistochemistry for TH and microtubule-associated protein 2 identified the majority of TH-positive processes in either culture system as dendrites. Individual MES but not HYP DA neurons were also found to generate axons. Western analysis showed that between 1 and 21 DIV the concentration of TH protein increased 2-fold in MES and 4-fold in HYP cultures. After 21 DIV the concentration of TH protein in MES cultures was twice that found in cultures of HYP. In the period between 1 and 21 DIV levels of tetrahydrobiopterin (BH4) increased by 6-fold in MES and 20-fold in HYP cultures. After 21 DIV BH4 content was 3-fold higher in HYP than in MES cultures. The abundance of the mRNA encoding for GTP cyclohydrolase I, the rate-limiting enzyme in BH4 biosynthesis, was similar in MES and HYP cultures despite this difference in BH4 levels. In contrast, TH mRNA was 4-fold more abundant in MES than in HYP cultures. Treatment of MES cultures with the DA neuron toxin 1-methyl-4-phenylpyridinium decreased DA cell numbers, TH protein content and BH4 levels, demonstrating that BH4 is localized primarily to DA neurons. Similar treatment of HYP cultures did not effect any of these parameters. Steady-state levels of DA and the rate of DA synthesis were both 3-fold higher in MES than in HYP cultures. A 95% decline in BH4 content produced by inhibiting BH4 biosynthesis resulted in 64% and 84% declines in the rate of MES and HYP DA synthesis, respectively. Overall, these observations indicate that, with the exception of the capacity to synthesize DA, DA neurons in MES and HYP cultures share few common properties.
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PMID:A comparison of the developing dopamine neuron phenotype in cultures of embryonic rat mesencephalon and hypothalamus. 782 64

Cultures of neonatal rat superior cervical ganglia (SCG) were used to test the hypothesis that the cytokines leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF) control GTP cyclohydrolase I (GTPCH) gene expression and 5,6,7,8-tetrahydrobiopterin (BH4) content as traits of the noradrenergic phenotype. Treatment for 7 days with 1 ng/ml of LIF was found to produce the characteristic switch in the SCG neurotransmitter phenotype reported by others, as evidenced by a 60% decline in tyrosine hydroxylase. (TH) activity and a 75% increase in choline acetyltransferase activity. This LIF treatment paradigm decreased BH4 levels in a concentration-dependent manner, with a maximal decline of 60% observed at 1 ng/ml. Analysis of the time course of this response indicated that LIF decreased BH4 levels by 60% following 3-7 days of treatment. Treatment of cultures with CNTF (2 ng/ml) resulted in a decline in BH4 levels that was of equal magnitude and followed the same time course as that produced by LIF. The LIF-dependent decline in BH4 levels resulted from a reduction in GTPCH enzyme activity, which decreased by 75% following 7 days of treatment. Nuclease protection assays of RNA extracted from cells treated for 7 days with 2 ng/ml of LIF or CNTF detected a 78-96% reduction in GTPCH mRNA content relative to beta-actin mRNA content. Concomitant decreases in TH and GTPCH gene expression in response to LIF or CNTF demonstrate a coordinated regulation of gene expression for this BH4-dependent enzyme and the rate-limiting enzyme in the synthesis of its essential cofactor, BH4. Moreover, these results indicate that GTPCH gene expression in SCG neurons should be regarded as a trait of the noradrenergic phenotype.
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PMID:Regulation of GTP cyclohydrolase I gene expression and tetrahydrobiopterin content in cultured sympathetic neurons by leukemia inhibitory factor and ciliary neurotrophic factor. 863 80

Gene transfer of tyrosine hydroxylase (TH) in animal models of Parkinson's disease (PD), using either genetically modified cells or recombinant virus vectors, has produced partial restoration of behavioral and biochemical deficits. The limited success of this approach may be related to the availability of the cofactor, tetrahydrobiopterin (BH4), because neither the dopamine-depleted striatum nor the cells used for gene transfer possess a sufficient amount of BH4 to support TH activity. To determine the role of BH4 in gene therapy, fibroblast cells transduced with the gene for TH were additionally modified with the gene for GTP cyclohydrolase l; an enzyme critical for BH4 synthesis. In contrast to cells transduced with only TH, doubly transduced fibroblasts spontaneously produced both BH4 and 3, 4-dihydroxy-L-phenylalanine. To examine further the importance of GTP cyclohydrolase I in gene therapy for PD, in vivo micro-dialysis was used to assess the biochemical changes in the dopamine-denervated striatum containing grafts of genetically modified fibroblasts. Only denervated striata grafted with fibro-blasts possessing both TH and GTP cyclohydrolase I genes displayed biochemical restoration. However, no significant differences from controls were observed in apomorphine-induced rotation. This is partly attributable to a limited duration of gene expression in vivo. These differences between fibroblasts transduced with TH alone and those additionally modified with the GTP cyclohydrolase I gene indicate that BH4 is critical for biochemical restoration in a rat model of PD and that GTP cyclohydrolase I is sufficient for production of BH4.
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PMID:Double transduction with GTP cyclohydrolase I and tyrosine hydroxylase is necessary for spontaneous synthesis of L-DOPA by primary fibroblasts. 869 55

The regulation of catecholamine and tetrahydrobiopterin synthesis was investigated in cultured rat pheochromocytoma PC12 cells following treatments with nerve growth factor (NGF), epidermal growth factor (EGF) and interferon-gamma (IFN-gamma). NGF and EGF, but not IFN-gamma, caused an increase after 24 h in the levels of BH4 and catecholamines, and the activities of tyrosine hydroxylase and GTP cyclohydrolase, the rate-limiting enzymes in catecholamine and BH4 synthesis, respectively. Actinomycin D, a transcriptional inhibitor, blocked treatment-induced elevations in tyrosine hydroxylase and GTP cyclohydrolase activities. NGF, EGF or IFN-gamma did not affect the activity of sepiapterin reductase, the final enzyme in BH4 biosynthesis. Rp-cAMP, an inhibitor of cAMP-mediated responses, blocked the induction of tyrosine hydroxylase by NGF or EGF; inhibition of protein kinase C partially blocked the EGF effect, but not the NGF effect, NGF also induced GTP cyclohydrolase in a cAMP-dependent manner, while the EGF effect was not blocked by Rp-cAMP or protein kinase C inhibitors. Sphingosine induced GTP cyclohydrolase in a protein kinase C-independent manner without affecting tyrosine hydroxylase activity. Our results suggest that both tyrosine hydroxylase and GTP cyclohydrolase are induced in a coordinate and transcription-dependent manner by NGF and EGF, while conditions exist where the induction of tyrosine hydroxylase and GTP cyclohydrolase is not coordinately regulated.
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PMID:Regulation of tyrosine hydroxylase and tetrahydrobiopterin biosynthetic enzymes in PC12 cells by NGF, EGF and IFN-gamma. 872 83


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