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)

In digitonin-permeabilized bovine adrenal medullary cells, Ca2+ (0.1-1.0 microM) caused an activation of tyrosine hydroxylase which was dependent on the presence of ATP. This Ca2+-induced activation of the enzyme was observed even in the presence of optimal concentration of either cyclic AMP or 12-O-tetradecanoylphorbol-13-acetate (TPA) which by itself increased the enzyme activity. Calmodulin inhibitors, trifluoperazine (TFP) and N-(6-aminohexyl)-5-chloro-1-naphtalenesulfonamide (W-7), had little effect on the Ca2+-evoked activation of enzyme. These results suggest that micromolar concentrations of Ca2+ activate the activity of tyrosine hydroxylase probably through a Ca2+-dependent phosphorylation in digitonin-permeabilized adrenal medullary cells although the protein kinase(s) responsible for it still remains to be determined.
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PMID:Activation of tyrosine hydroxylase by micromolar concentrations of calcium in digitonin-permeabilized adrenal medullary cells. 288 62

Incubation of cultured bovine adrenal medullary cells in Na+-free sucrose medium or in Na+-free Cs+ medium enhanced the synthesis of 14C-catecholamines from [14C]tyrosine about two- to threefold or sixfold, respectively. The increment of 14C-catecholamine synthesis produced by Na+-free medium was partially dependent on the presence of Ca2+ in the medium. Dibutyryl cyclic AMP also stimulated the synthesis of 14C-catecholamines in adrenal medullary cells, and the effects of Na+ removal and dibutyryl cyclic AMP (5 mM) on the synthesis were almost additive. The intracellular pH measured by using a weak acid 5,5-dimethyloxazolidine-2,4-dione was 7.14 in control cells and when Na+ was replaced by sucrose or Cs+, it shifted down to 6.56 or 5.66, respectively. The fall in intracellular pH and the stimulation of 14C-catecholamine synthesis were similarly dependent on the concentration of Na+ in the medium. The optimal pH of soluble tyrosine hydroxylase was 5.5-6.0 both in control cells and in cells incubated in Na+-free medium. These results suggest that removal of extracellular Na+ increases the synthesis of catecholamines, at least in part, by shifting the intracellular pH toward the optimal pH of tyrosine hydroxylase.
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PMID:Intracellular pH and catecholamine synthesis in cultured bovine adrenal medullary cells: effect of extracellular Na+ removal. 289 Jul 12

To elucidate the source and physiological significance of plasma 3,4-dihydroxyphenylalanine, the immediate product of the rate-limiting step in catecholamine biosynthesis, plasma 3,4-dihydroxyphenylalanine was quantified in conscious rats after administration of reserpine, desipramine, clorgyline, or forskolin, treatments that affect tyrosine hydroxylase activity. Plasma 3,4-dihydroxyphenylalanine was also examined during infusions of norepinephrine with or without clorgyline, reserpine, or desipramine pretreatment. After reserpine, the plasma 3,4-dihydroxyphenylalanine level decreased by 22% and then increased by 40%, a result consistent with modulation of tyrosine hydroxylase activity first by an increased axoplasmic norepinephrine content and then by depletion of norepinephrine stores. After desipramine, the plasma 3,4-dihydroxyphenylalanine level decreased by 20%, reflecting the depressant effect of neuronal uptake blockade on norepinephrine turnover. Forskolin increased the plasma 3,4-dihydroxyphenylalanine level by 30%, consistent with activation of tyrosine hydroxylase by cyclic AMP-dependent phosphorylation. Acute administration of clorgyline was without effect on the plasma 3,4-dihydroxyphenylalanine level. Norepinephrine infusions decreased the plasma 3,4-dihydroxyphenylalanine concentration, as expected from end-product inhibition of tyrosine hydroxylase. Pretreatment with desipramine prevented the norepinephrine-induced decrease in plasma dihydroxyphenylalanine content, indicating that inhibition of tyrosine hydroxylase required neuronal uptake of norepinephrine. Both reserpine and clorgyline augmented the norepinephrine-induced decrease in plasma 3,4-dihydroxyphenylalanine level, suggesting that retention of norepinephrine in the axoplasm--due to inhibition of norepinephrine sequestration into storage vesicles or catabolism--caused further inhibition of tyrosine hydroxylase. Changes in plasma 3,4-dihydroxyphenylalanine concentration during norepinephrine infusions were negatively correlated with those in plasma 3,4-dihydroxyphenylglycol level, a finding consistent with modulation of tyrosine hydroxylase activity by axoplasmic norepinephrine. In reserpinized animals, clorgyline and norepinephrine infusion together decreased the plasma 3,4-dihydroxyphenylalanine content by 50%, a result demonstrating that hydroxylation of tyrosine was depressed by at least half. The results indicate that quantification of plasma 3,4-dihydroxyphenylalanine can provide a simple and direct approach for examination of the rate-limiting step in catecholamine biosynthesis.
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PMID:Source and physiological significance of plasma 3,4-dihydroxyphenylalanine in the rat. 290 61

Tyrosine hydroxylase activity is reversibly modulated by the actions of a number of protein kinases and phosphoprotein phosphatases. A previous report from this laboratory showed that low-molecular-weight substances present in striatal extracts lead to an irreversible loss of tyrosine hydroxylase activity under cyclic AMP-dependent phosphorylation conditions. We report here that ascorbate is one agent that inactivates striatal tyrosine hydroxylase activity with an EC50 of 5.9 microM under phosphorylating conditions. Much higher concentrations (100 mM) fail to inactivate the enzyme under nonphosphorylating conditions. Isoascorbate (EC50, 11 microM) and dehydroascorbate (EC50, 970 microM) also inactivated tyrosine hydroxylase under phosphorylating but not under nonphosphorylating conditions. In contrast, ascorbate sulfate was inactive under phosphorylating conditions at concentrations up to 100 mM. Since the reduced compounds generate several reactive species in the presence of oxygen, the possible protecting effects of catalase, peroxidase, and superoxide dismutase were examined. None of these three enzymes, however, afforded any protection against inactivation. We also examined the effects of ascorbate and its congeners on the activity of tyrosine hydroxylase purified to near homogeneity from a rat pheochromocytoma. This purified enzyme was also inactivated by the same agents that inactivated the impure corpus striatal enzyme. Under conditions in which ascorbate almost completely abolished enzyme activity, we found no indication for significant proteolysis of the purified enzyme as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. We also found that pretreatment of PC12 cells in culture for 4 h with 1 mM ascorbate, dehydroascorbate, or isoascorbate (but not ascorbate sulfate) also decreased tyrosine hydroxylase activity 25-50%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inactivation of tyrosine hydroxylase activity by ascorbate in vitro and in rat PC12 cells. 290 63

Activation of neurotransmitter receptors can regulate transcription in postsynaptic cells through the actions of second messengers. Trans-synaptic regulation of transcription appears to be an important mechanism controlling the synthesis of molecules involved in neuronal signaling, especially neuropeptides. Proenkephalin, vasoactive intestinal polypeptide, and somatostatin have been shown to be transcriptionally regulated by the second messenger, cyclic AMP (cAMP), as has the catecholamine synthesizing enzyme tryosine hydroxylase. cAMP-inducible elements have been mapped within these genes, and trans-acting factors which bind to several such elements have been identified. With the discovery that individual neurons generally contain multiple transmitters within their synaptic terminals, it has become important to understand in detail the mechanisms by which the synthesis of transmitters can be coregulated. Here we compare the structure and function of the proenkephalin cAMP-inducible enhancer with the mapped cAMP-inducible elements of the vasoactive intestinal polypeptide, somatostatin, and tyrosine hydroxylase genes and a putative cAMP-inducible element in the proto-oncogene c-fos. We have previously shown that the proenkephalin enhancer is composed of two different elements, ENKCRE-1 and ENKCRE-2. We show here that one of these, ENKCRE-2, is structurally similar to elements found within the vasoactive intestinal polypeptide, somatostatin, and tyrosine hydroxylase genes and binds a trans-acting factor that is competed for both in cotransfection experiments (in vivo) and in DNase I footprint assays (in vitro) by these other elements. The c-fos element has similar structural requirements to confer transcriptional induction by cAMP but competes less strongly. Protein purified by affinity chromatography with the ENKCRE-2 sequence binds to each of these elements. A second element within the proenkephalin cAMP-inducible enhancer, ENKCRE-1, binds a factor that is not competed for by these other genes and is therefore distinct. This analysis suggests a potential mechanism of transcriptional coregulation of the neuronally expressed genes investigated in this study and also demonstrates that multiple factors are involved in transcriptional activation by cAMP.
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PMID:A common trans-acting factor is involved in transcriptional regulation of neurotransmitter genes by cyclic AMP. 290 36

Incubation of rat striatal synaptosomes with the adenosine receptor agonist 2-chloroadenosine (2-CADO) produced a concentration-dependent increase of dopamine (DA) synthesis (about 50% of control value). The effect was not additive with the stimulation produced by either 10 microM forskolin or 2 mM dibutyryl cyclic AMP. Pretreatment of striatal synaptosomes with 2-CADO produced an activation of tyrosine hydroxylase (TH) which withstood washing and lysing of the tissue. This activation was largely independent of the presence of Ca2+ ion in the preincubation medium and, when analyzed as a function of different concentrations of the pterin cofactor 6-methyl-5,6,7,8-tetrahydropterin (0.08-0.4 mM), it was associated with an apparent increase in the Vmax of the enzyme. Quinpirole, a selective D2 DA receptor agonist, reduced control synaptosomal DA synthesis and caused a persistent inhibition of TH activity. When added together with 2-CADO, quinpirole depressed the stimulation of DA synthesis and TH activity produced by the adenosine analog. The effect of quinpirole was stereospecifically antagonized by the D2 DA antagonist sulpiride. Quinpirole also inhibited the activation of TH elicited by a submaximal concentration of forskolin, but not that produced by dibutyryl cyclic AMP. The inhibitory effect of quinpirole on basal and 2-CADO-stimulated TH activities was mimicked by DA. These results indicate that presynaptic DA autoreceptors and adenosine A2 receptors interact antagonistically in controlling DA synthesis in rat striatal synaptosomes presumably by exerting opposite inputs on a presynaptic adenylate cyclase system.
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PMID:Evidence that adenosine A2 and dopamine autoreceptors antagonistically regulate tyrosine hydroxylase activity in rat striatal synaptosomes. 290 90

In isolated bovine adrenal medullary cells, the phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA), an activator of protein kinase C, stimulated [14C]catecholamine synthesis from [14C]tyrosine, but not from [14C]DOPA. This stimulatory effect of TPA on [14C]catecholamine synthesis was not dependent upon extracellular Ca2+, and TPA did not affect the uptake of 45Ca2+ or the release of catecholamine by the cells. TPA also did not affect the intracellular cyclic AMP (cAMP) level. 4 alpha-Phorbol 12, 13-didecanoate, which is not an activator of protein kinase C, did not stimulate the synthesis of [14C]catecholamine from [14C]tyrosine. The stimulatory effect of TPA on [14C]catecholamine synthesis was additive with that of carbamylcholine, but not with that of dibutyryl cAMP (DB-cAMP). From these results, it was suggested that protein kinase C is involved in the regulation of tyrosine hydroxylase activity and that this regulatory mechanism might be similar to that involving cAMP.
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PMID:Phorbol ester stimulates catecholamine synthesis in isolated bovine adrenal medullary cells. 299 23

Many hormones and neurotransmitters exert their biological effects by increasing the levels of Ca2+ and 1,2-diacylglycerol in their target cells. Major agonists that act in this way are epinephrine and norepinephrine, acetylcholine, vasopressin, cholecystokinin, and angiotensin II. These and other Ca2+-mobilizing agonists may also produce effects that are not mediated by Ca2+ or diacylglycerol, but involve separate receptors and an increase or decrease in cyclic AMP. The general mechanisms by which Ca2+-mobilizing agonists induce their physiological responses are depicted in Fig. 12. These responses appear to involve an initial mobilization of Ca2+ from endoplasmic reticulum and perhaps other intracellular Ca2+ stores, followed by alterations in the flux of Ca2+ across the plasma membrane. The Ca2+ changes are consistently associated with increased turnover of cellular phosphoinositides. The most rapid response is breakdown of phosphatidylinositol 4,5-P2 in the plasma membrane, and there is much evidence that this involves a guanine-nucleotide-binding regulatory protein similar to those involved in the regulation of adenylate cyclase. Myo-inositol 1,4,5-P3 produced by phosphatidylinositol 4,5-P2 breakdown rapidly releases Ca2+ from endoplasmic reticulum, and it is likely that it is the long-sought second message for the Ca2+-dependent hormones. 1,2-Diacylglycerol, the other product of phosphatidylinositol 4,5-P2 breakdown, also acts as a second message in that it activates protein kinase C, a Ca2+-phospholipid-dependent protein kinase, by lowering its requirement for Ca2+. The cellular substrates for protein kinase C and its role in the different physiological responses to the Ca2+-mediated agonists are currently being defined. The major intracellular target for Ca2+ is the Ca2+-dependent regulatory protein calmodulin. This binds Ca2+ with high affinity, and the resulting complex interacts with a variety of enzymes and other cellular proteins, modifying their activities. A major target is the multifunctional calmodulin-dependent protein kinase that phosphorylates and alters the activities of many proteins, for example, glycogen synthase and tyrosine hydroxylase. Calcium ions may also stimulate calmodulin-dependent protein kinases that are more specific, such as phosphorylase kinase and myosin light-chain kinase. Other important Ca2+-calmodulin targets are the microtubule-associated proteins, but it is likely that many more will be found.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms involved in calcium-mobilizing agonist responses. 302 85

In isolated bovine adrenal medullary cells, vasoactive intestinal polypeptide (VIP) stimulated 14C-catecholamine synthesis from 14C-tyrosine, but not from 14C-DOPA. This stimulatory effect of VIP on 14C-catecholamine synthesis was not dependent upon extracellular Ca2+. VIP did not affect the intracellular cyclic AMP (cAMP) level. The stimulatory effect of VIP on 14C-catecholamine synthesis was additive with that of carbamylcholine, which was dependent upon extracellular Ca2+, but not with that of phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA), an activator of protein kinase C. Moreover, 1-(isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7), an inhibitor of protein kinase C, inhibited not only TPA-stimulated, but also VIP-stimulated 14C-catecholamine synthesis from 14C-tyrosine. These results suggested that VIP stimulated catecholamine synthesis by activation of tyrosine hydroxylase and that protein kinase C was involved in this stimulatory mechanism.
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PMID:Stimulation by vasoactive intestinal polypeptide of catecholamine synthesis in isolated bovine adrenal chromaffin cells. Possible involvement of protein kinase C. 310 75

Differential screening of cDNA libraries was used to detect and prepare probes for mRNAs that are regulated in PC12 rat pheochromocytoma cells by long-term (2-week) treatment with nerve growth factor (NGF). In response to NGF, PC12 cells change from a chromaffin cell-like to a sympathetic-neuron-like phenotype. Thus, one aim of this study was to identify NGF-regulated mRNAs that may be associated with the attainment of neuronal properties. Eight NGF-regulated mRNAs are described. Five of these increase 3- to 10-fold and three decrease 2- to 10-fold after long-term NGF exposure. Each mRNA was characterized with respect to the time course of the NGF response, regulation by agents other than NGF, and rat tissue distribution. Partial sequences of the cDNAs were used to search for homologies to known sequences. Homology analysis revealed that one mRNA (increased 10-fold) encodes the peptide thymosin beta 4 and a second mRNA (decreased 2-fold) encodes tyrosine hydroxylase. Another of the increased mRNAs was very abundant in sympathetic ganglia, barely detectable in brain and adrenals, and undetectable in all other tissues surveyed. One of the decreased mRNAs, by contrast, was very abundant in the adrenals and nearly absent in the sympathetic ganglia. With the exception of fibroblast growth factor, which is the only other agent known to mimic the differentiating effects of NGF on PC12 cells, none of the treatments tested (epidermal growth factor, insulin, dibutyryl cyclic AMP, dexamethasone, phorbol ester, and depolarization) reproduced the regulation observed with NGF. These and additional findings suggest that the NGF-regulated mRNAs may play roles in the establishment of the neuronal phenotype and that the probes described here will be useful to study the mechanism of action of NGF and the development and differentiation of neurons.
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PMID:Identification and characterization of mRNAs regulated by nerve growth factor in PC12 cells. 367 Mar 9


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