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)

Recent studies have demonstrated that chronic stress increases the firing rate and expression of tyrosine hydroxylase (TH) in neurons of the locus coeruleus (LC), the major noradrenergic nucleus in brain. The present study was undertaken to examine the influence of chronic stress and other treatments known to influence the activity of LC neurons on the cyclic AMP (cAMP) second messenger system in these neurons. Chronic (5 days) cold exposure significantly increased levels of TH immunoreactivity in the LC, as previously reported, but not in substantia nigra (SN) or ventral tegmentum (VT), two dopaminergic nuclei studied for comparison. Chronic cold exposure increased levels of cAMP-dependent protein kinase activity in soluble, but not particulate, fractions of the LC, and increased basal and GTP- and forskolin-stimulated adenylate cyclase activity in this brain region. In contrast, levels of the protein kinase and adenylate cyclase in VT, SN, and frontal cortex were not significantly influenced by cold exposure. To study further the relationship between regulation of LC firing rate, TH expression, and the cAMP system in the LC, other treatments known to influence TH were examined. Reserpine treatment, shown previously to increase levels of TH, was found to increase both LC firing rate and levels of soluble cAMP-dependent protein kinase activity in the LC. 6-Hydroxydopamine, shown previously to increase levels of TH and firing rate of LC neurons, also increased soluble levels of protein kinase activity. Other treatments known to either increase (adrenalectomy) or decrease (chronic imipramine) levels of TH in the LC were also found to increase or decrease, respectively, levels of cAMP-dependent protein kinase activity in this brain region.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Coordinate regulation of the cyclic AMP system with firing rate and expression of tyrosine hydroxylase in the rat locus coeruleus: effects of chronic stress and drug treatments. 134 39

Lesioning of neonatal rats with the neurotoxin 6-hydroxydopamine (6-OHDA) reduced striatal dopamine (DA) levels to 3% of control levels and produced marked increases in the behavioral effects of the selective D1-DA receptor agonist SKF-38393 in these animals when tested as adults. However, no differences were observed, either in basal or D1-DA-stimulated striatal cAMP formation or in forskolin-stimulated or GTP-stimulated cAMP production, between control and lesioned animals. C-fos-like immunoreactivity after SKF-38393 was significantly greater in dorsolateral vs. ventromedial aspects of the striatum in lesioned animals. Like the c-fos response, augmented electrophysiological responsiveness to SKF-38393 occurred in lesioned rats in lateral, but not medial, portions of the striatum. No differences were found in nucleus accumbens in sensitivity to SKF-38393 between control and lesioned rats. Although autoradiographic determination of D1-DA receptor binding throughout the striatum and nucleus accumbens revealed no differences between unlesioned and lesioned rats, tyrosine hydroxylase-like immunoreactivity was reduced with a regional distribution inversely related to c-fos-like immunohistochemical expression. These findings demonstrate that regionally enhanced electrophysiological sensitivity of striatal neurons to D1-DA receptor agonists after neonatal 6-OHDA-induced lesions is associated with regional changes in c-fos-like immunoreactivity and tyrosine hydroxylase-like immunohistochemistry, but not with changes in D1-DA receptor autoradiography or D1-DA-stimulated adenylyl cyclase activity. Such regional consequences of 6-OHDA-induced lesions in neonates may contribute to the unique behavioral patterns observed when these rats are challenged with L-dopa or D1-DA agonists as adults.
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PMID:Augmented sensitivity of D1-dopamine receptors in lateral but not medial striatum after 6-hydroxydopamine-induced lesions in the neonatal rat. 136 76

Repeated electroconvulsive shock (ECS) treatment (once per day for 7 days) produced a significant increase in tyrosine hydroxylase activity, GTP-cyclohydrolase activity and tetrahydrobiopterin (BH4) levels in the locus ceruleus and hippocampus from 1 to 4 days after the last treatment. These changes may be responsible for, or contribute to, the antidepressant effect of ECS treatment.
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PMID:The effects of electroconvulsive shock on catecholamine function in the locus ceruleus and hippocampus. 168 84

Chronic (3 months) lead exposure increased the quinonoid dihydropteridine reductase activity and the tetrahydrobiopterin content but did not affect the GTP-cyclohydrolase activity and the dihydrobiopterin content. These results suggest that lead intoxication may enhance dopamine metabolism in neostriatum by increasing the content of tetrahydrobiopterin, the regulating cofactor of tyrosine hydroxylase activity.
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PMID:Effect of chronic lead exposure on biopterin metabolism in the rat neostriatum. 235 44

Pheochromocytoma cells (clone PC-12) were treated with 6-aminonicotinamide. Tetrahydrobiopterin content and DOPA production of the cells were determined by reverse-phase HPLC and subsequent electrochemical detection. The same chromatographic system was used to determine total biopterin (tetrahydrobiopterin, dihydrobiopterin and quinoide dihydrobiopterin) by fluorescence detection. Tetrahydrobiopterin plays a decisive role as cofactor of tyrosine hydroxylase for the biosynthesis of DOPA and dopamine. Addition of 6-aminonicotinamide to the culture medium resulted in the accumulation of 6-phosphogluconate, suggesting that PC-12 cells synthesize 6-aminonicotinamide-adenine-dinucleotide-phosphate (6-ANADP) by a glycohydrolase localized in the endoplasmic reticulum. This substance is known to be a strong inhibitor of 6-phosphogluconate dehydrogenase and leads to a blockade of the pentose phosphate pathway. In our experiments, the synthesis of biopterins was depressed after application of 6-aminonicotinamide. The decrease of intracellular tetrahydrobiopterin and total biopterin by 6-aminonicotinamide at different concentrations was strongly correlated with a reduced cellular DOPA production. The decreased content of biopterin cofactor was compensated by addition of the precursor sepiapterin, indicating that the NADPH2-dependent reductases in biopterin synthesis are not inhibited by the antimetabolite. However, DOPA production remained suppressed at the same time. After application of NADH2, we observed an increased DOPA production though the decreased biopterin levels remained almost unchanged. The results imply that the first step in the synthesis of biopterin from GTP as well as the recycling pathways of the oxidized cofactor might be the site of action of the antimetabolite.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of biopterin synthesis and DOPA production in PC-12 pheochromocytoma cells induced by 6-aminonicotinamide. 252 71

During investigations of the regulation of tyrosine hydroxylase (TH) by protein phosphorylation, a novel protein kinase activity has been discovered in rat pheochromocytoma. Originally detected as a trace contaminant in preparations of highly purified TH, this novel kinase activity phosphorylated TH at serine 8 in the proline-rich amino-terminal region of the enzyme. This particular site is not phosphorylated by, nor is the amino acid sequence surrounding this site selective for, any of the classical (i.e. well characterized) protein kinases. In this report, we describe the identification, characterization, and partial purification of this novel protein kinase. By utilizing a synthetic peptide corresponding to the amino-terminal region of TH, a selective assay for this protein kinase was developed. The kinase activity utilized ATP and magnesium, although GTP could also be utilized as a phosphate donor. The kinase activity was found to co-purify with TH activity through ammonium sulfate precipitation and DEAE-cellulose chromatography and could be only partially resolved from TH by heparin-agarose affinity chromatography. Substantial kinase activity could be resolved from TH by phosphocellulose chromatography. The novel kinase migrates as a protein with a molecular mass of approximately 45 kDa on gel permeation chromatography as well as sucrose density gradient centrifugation. Studies of site specificity indicate that this Ser/Thr kinase activity appears to be directed by an adjacent (carboxyl-terminal) proline residue, exhibiting a minimal recognition sequence of -X-Ser/Thr-Pro-X-. In addition to TH, this proline-directed protein kinase will also phosphorylate synapsin I, histone H1, and glycogen synthase, suggesting that this kinase may have multiple substrates in vivo. Additional findings indicate that the activity of proline-directed protein kinase is increased transiently in PC12 pheochromocytoma cells following treatment with nerve growth factor. Distinctions between this novel kinase and other well characterized protein kinases can be made on the basis of phosphorylation site specificity, chromatographic behavior, and physical characteristics.
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PMID:Identification of a novel proline-directed serine/threonine protein kinase in rat pheochromocytoma. 257 Jul 79

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

Selective modification of the tetrahydrobiopterin levels in cultured chromaffin cells were followed by changes in the rate of tyrosine hydroxylation. Addition of sepiapterin, an intermediate on the salvage pathway for tetrahydrobiopterin synthesis, rapidly increased intracellular levels of tetrahydrobiopterin and elevated the rate of tyrosine hydroxylation in the intact cell. Tyrosine hydroxylation was also enhanced when tetrahydrobiopterin was directly added to the incubation medium of intact cells. When the cultured chromaffin cells were treated for 72 h with N-acetylserotonin, an inhibitor of sepiapterin reductase, tetrahydrobiopterin content and the rate of tyrosine hydroxylation were decreased. Addition of sepiapterin or N-acetylserotonin had no consistent effect on total extractable tyrosine hydroxylase activity or on catecholamine content in the cultured chromaffin cells. Three-day treatment of chromaffin cell cultures with compounds that increase levels of cyclic AMP (forskolin, cholera toxin, theophylline, dibutyryl- and 8-bromo cyclic AMP) increased total extractable tyrosine hydroxylase activity and GTP-cyclohydrolase, the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin. Tetrahydrobiopterin levels and intact cell tyrosine hydroxylation were markedly increased after 8-bromo cyclic AMP. The increase in GTP-cyclohydrolase and tetrahydrobiopterin induced by 8-bromo cyclic AMP was blocked by the protein synthesis inhibitor cycloheximide. Agents that deplete cellular catecholamines (reserpine, tetrabenazine, and brocresine) increased both total tyrosine hydroxylase and GTP-cyclohydrolase activities, although treating the cultures with reserpine or tetrabenazine resulted in no change in cellular levels of cyclic AMP. Brocresine and tetrabenazine increased tetrahydrobiopterin levels, but the addition of reserpine to the cultures decreased catecholamine and tetrahydrobiopterin content and resulted in a decreased rate of intact cell tyrosine hydroxylation in spite of the increased activity of the total extractable enzyme. These data indicate that in cultured chromaffin cells GTP-cyclohydrolase activity like tyrosine hydroxylase activity is regulated by both cyclic AMP-dependent and cyclic AMP-independent mechanisms and that the intracellular level of tetrahydrobiopterin is one of the many factors that control the rate of tyrosine hydroxylation.
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PMID:Regulation of guanosine triphosphate cyclohydrolase and tetrahydrobiopterin levels and the role of the cofactor in tyrosine hydroxylation in primary cultures of adrenomedullary chromaffin cells. 286 7

Tyrosine hydroxylase phosphatase activity in rat caudate nucleus was separated into three peaks by chromatography on DEAE-cellulose. [32P]Tyrosine hydroxylase phosphorylated by cyclic AMP-dependent protein kinase was dephosphorylated only by the major peak eluting at 0.3 M NaCl, while tyrosine hydroxylase phosphorylated by Ca2+-calmodulin-dependent protein kinase was also dephosphorylated by two calcium-inhibited phosphatases. The Vmax of the enzyme in the major DEAE peak was increased by 10 microM tetrahydrobiopterin (BH4) from 0.78 to 5.0 fmol min-1 mg-1 while the Km was only slightly affected, increasing from 45 to 62 pM. The activation could not be reversed by dilution. On Sephadex G-200, the enzyme was found to consist of two major forms with molecular masses of 420 and 100 kDa. In contrast to the activation of liver phosphatases by freezing with beta-mercaptoethanol, activation by tetrahydrobiopterin was not associated with a shift in the molecular weight of the phosphatase to lower molecular weight forms. Other reduced pterins, including tetrahydroneopterin, 6-methyltetrahydropterin, and 5-methyltetrahydrofolate, also activated the enzyme, while oxidized pterins had no effect. GTP, the metabolic precursor of tetrahydrobiopterin, was a potent inhibitor of the phosphatase reaction, inhibiting by 65% at a concentration of 1 microM. These findings suggest a close regulatory interrelationship between the tetrahydrobiopterin synthetic pathway and catecholamine biosynthesis.
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PMID:Activation of rat caudate tyrosine hydroxylase phosphatase by tetrahydropterins. 289 Jun 38

We have developed a cell-free assay to detect and characterize nerve growth factor (NGF)-activated protein kinase activity. Cultured PC12 cells were briefly exposed to NGF, and extracts of these were assayed for phosphorylating activity using exogenously added tyrosine hydroxylase as substrate. Tyrosine hydroxylase was employed since it is an endogenous substrate of NGF-regulated kinase activity and is activated by phosphorylation. In the cell-free assay, extracts prepared from NGF-treated cells yielded a 2-3-fold greater incorporation of phosphate into tyrosine hydroxylase as compared with extracts of control, NGF-untreated cells. Activation did not occur, however, if NGF was added directly to cell extracts. The NGF-stimulated phosphorylating activity appeared to be due to regulation of a protein kinase rather than of a phosphoprotein phosphatase. Characterization of the kinase (designated as kinase N) showed that it is soluble, is detectably activated within 1-3 min after cells are exposed to NGF and maximally activated by 10 min, is half-maximally activated with 0.5 nM NGF and maximally activated with 1 nM NGF, is detectable in the presence of either Mg2+ or Mn2+ but does not require Ca2+, does not require nonmacromolecular cofactors, can use histone H1 as a substrate, and exhibits a 2-fold increase in apparent Vmax in response to NGF but does not undergo a significant change in apparent Km for either ATP or GTP. A number of characteristics of kinase N were assessed including susceptibility to inhibitors, substrate specificity, cofactor requirements, ATP dependence, and lack of down-regulation by prolonged expose to a phorbol ester. These studies indicated that it lacks tyrosine kinase activity and is distinct from a variety of well-characterized protein kinases including cAMP-dependent protein kinase, protein kinase C (Ca2+/phospholipid-dependent enzyme), Ca2+/calmodulin-dependent kinase, and casein kinase II. Preliminary purification data show that the kinase has a basic pI and that it has an apparent Mr of 22,000-25,000. The only amino acid in tyrosine hydroxylase found to be phosphorylated by the semipurified kinase is serine.
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PMID:Cell-free detection and characterization of a novel nerve growth factor-activated protein kinase in PC12 cells. 358 24


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