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)

1. The effects of the protein kinase C inhibitor, Ro 31-8220, on the responses of cultured bovine adrenal chromaffin cells to nicotine, phorbol 12, 13-dibutyrate (PDBu) and K+ have been investigated. 2. Tyrosine hydroxylase activity was measured in situ in intact cells by measuring 14CO2 evolved following the hydroxylation and rapid decarboxylation of [14C]-tyrosine offered to the cells. Secretion of endogenous adrenaline and noradrenaline was measured by use of h.p.l.c. with electrochemical detection. Cyclic AMP levels were measured in cell extracts by RIA. 3. Ro 31-8220 produced a concentration-dependent inhibition of 300 nM PDBu-stimulated tyrosine hydroxylase activity with an IC50 of < 2 microM and complete inhibition at 10 microM. It had no effect on the responses to forskolin. 4. Ro 31-8220 produced a concentration-dependent inhibition of 5 microM nicotine-stimulated tyrosine hydroxylase activity, adrenaline and noradrenaline secretion and cellular cyclic AMP levels, with an IC50 of about 3 microM and complete inhibition by 10 microM. At concentrations up to 10 microM, Ro 31-8220 had little or no effect on the corresponding responses to 50 mm K+. 5. A structural analogue of Ro 31-8220, bisindolylmaleimide V, that lacks activity as a protein kinase C inhibitor, had no effect up to 10 microM on PDBu-stimulated tyrosine hydroxylase activity or on nicotine-stimulated cyclic AMP levels or noradrenaline secretion and only marginal inhibitory effects on nicotine-stimulated tyrosine hydroxylase activity and adrenaline secretion. 6. A structurally related protein kinase C inhibitor, bisindolylmaleimide I, inhibited PDBu-stimulated tyrosine hydroxylase activity with an IC50 of < 1 microM and complete inhibition by 3 microM, but had essentially no effect on nicotine stimulated tyrosine hydroxylase activity or catecholamine secretion. 7. The results suggest that Ro 31-8220 is not only a protein kinase C inhibitor but is also a potent inhibitor of nicotinic receptor responses in adrenal chromaffin cells by a mechanism unrelated to protein kinase C inhibition. The results are consistent with Ro 31-8220 being a nicotinic receptor antagonist.
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PMID:Inhibition of nicotinic responses of bovine adrenal chromaffin cells by the protein kinase C inhibitor, Ro 31-8220. 888 29

We have localized the dopamine D1 receptor in rat retina using a subtype-specific monoclonal antibody. Immunolabelling can be detected in the inner and outer plexiform layers and in a number of cells in the inner nuclear layer. In the inner plexiform layer, labelled processes form four distinct horizontal bands and a series of patches. In order further to characterize the labelling pattern of the D1 receptor antibody, double-labelling experiments were performed with antibodies against population-specific neuronal markers in the retina. Antibodies against tyrosine hydroxylase, choline acetyltransferase, calretinin, calbindin, the glutamate transporter GLT-1, protein kinase C, recoverin and parvalbumin were co-applied with the D1 receptor antibody. With these cell markers we demonstrate that horizontal cells, at least three types of cone bipolar cells and a small number of amacrine cells are immunolabelled for the D1 receptor. In the inner plexiform layer, processes labelled by the D1 receptor antibody are co-stratified with processes labelled by the GLT-1 antibody. D1 receptor-labelled processes are not co-localized with the processes of amacrine cells and ganglion cells labelled by antibodies against tyrosine hydroxylase, choline acetyltransferase or calretinin. Our results indicate that dopamine D1 receptors are localized predominantly to horizontal cells and cone bipolar cells. Furthermore, the spatial disparity between dopaminergic processes and the site of the majority of D1 receptors supports the idea that in the retina dopamine acts as a neuromodulator that diffuses through extracellular space. The localization of D1 receptors to a number of identified cell types enables future physiological work to be directed towards specific synaptic circuits within the retina.
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PMID:Immunohistochemical localization of dopamine D1 receptors in rat retina. 895 93

Our previous studies indicate that, in the noncatecholamine (non-CA) neurons of the striatum, expression of the gene for the CA biosynthetic enzyme tyrosine hydroxylase (TH) can be initiated by the synergistic interaction of acidic fibroblast growth factor (aFGF) and a second partner molecule. In this study, we sought to determine whether the activators of protein kinase C (PKC) signaling pathways, either alone or in conjunction with various growth factors, is sufficient to induce TH in striatal neurons. We found that when the active beta from of 4 beta-12-O-tetradecanoylphorbol 13-acetate (TPA), but not the inactive alpha analogue, was incubated in the presence of aFGF, basic FGF, or brain-derived neurotrophic factor, TH expression was initiated. Activation of the PKC pathways alone (in the absence of growth factors) did not mimic these effects, suggesting that multiple pathway activation is required for novel TH expression. Although other specific activators of PKC were effective growth factor partners, TPA was the most potent with an ED50 of 0.008 muM. Conversely, inhibitors of protein kinases, such as H7, H8, or H89, prevented the expression of TH by aFGF and TPA. Because pretreatment with protein (cycloheximide) or RNA synthesis (amanitin and actinomycin D) inhibitors eliminated the inductive effect of aFGF and TPA, we conclude that de novo transcription and translation are necessary for the expression of TH after convergence of both PKC and growth factor pathways.
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PMID:Protein kinase C activators work in synergy with specific growth factors to initiate tyrosine hydroxylase expression in striatal neurons in culture. 900 41

Gene expression for tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, is regulated by reductions in oxygen tension (hypoxia). Hypoxia-induced regulation of the TH gene is due to the binding of specific transcription factors to specific sites on the 5' flanking region of the gene. The purpose of this study was to identify the second messenger system(s) responsible for regulation of the TH gene during hypoxia. Fura-2 fluorescence imaging of rat pheochromocytoma (PC12) cells, an O2-sensitive cell line, revealed that there is an increase in cytosolic calcium (Ca2+) associated with exposure to hypoxia. Based on the evidence that the transcription factors that bind to the TH promoter during hypoxia can also be induced by elevations in cytosolic Ca2+, the role of Ca2+ in the hypoxic regulation of the TH gene was explored. To assay the effect of hypoxia on TH gene expression, Northern blot analyses of total RNA were performed on PC12 cells exposed to hypoxia in the presence or absence of specific inhibitors. The addition of the L-type calcium channel blockers nifedipine or verapamil caused partial inhibition of the hypoxia-induced increase in TH mRNA. The increase in cytosolic Ca2+ during hypoxia was also only partially inhibited by addition of nifedipine. Importantly, chelation of extracellular Ca2+ completely inhibited the increase in TH mRNA by hypoxia. Pretreatment of PC12 cells with BAPTA/AM, an intracellular Ca2+ chelator, inhibited the hypoxic induction of TH gene expression in a dose-dependent manner. Addition of chelerythrine chloride (CHL), a protein kinase C inhibitor, to the media before exposure to hypoxia also resulted in an inhibition of TH induction by hypoxia. These results suggest that hypoxia regulates TH gene expression by a mechanism that is dependent on influx of calcium from the extracellular stores, partially but not exclusively through the L-type calcium channels. These results further suggest that a member of the PKC family is essential for this regulation.
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PMID:Regulation of tyrosine hydroxylase gene expression during hypoxia: role of Ca2+ and PKC. 902 34

Microglial activation selectively kills certain neuron populations in mixed neuronal/glial cultures, which may prove useful for modeling neurodegenerative diseases such as Parkinson's disease. In mesencephalic mixed neuronal/glial cultures, microglial activation by zymosan A killed more dopaminergic neurons, assessed by [3H]dopamine uptake and by counting tyrosine hydroxylase-immunoreactive neuron number, than did microglial activation by lipopolysaccharide (LPS). The additional toxicity of zymosan resulted from microglial protein kinase C (PKC) activation. Both zymosan and PMA, but not LPS, activated PKC in enriched microglial preparations. In the mixed neuronal/glial cultures, activation of PKC by phorbol myristate acetate (PMA) increased LPS-induced nitric oxide (NO; by nitrite measurements), but not zymosan-induced NO production, and increased LPS-induced dopaminergic neurotoxicity, but not zymosan-induced dopaminergic neurotoxicity. Additive effects of PMA and LPS, similar to zymosan effects alone, reflected activation of distinct neurotoxic pathways in the microglia. The NO synthase inhibitor N-nitro-L-arginine methyl ester (NAME) totally blocked the neurotoxicity of LPS, and partially blocked zymosan-induced neurotoxicity; NAME did not block the PKC component of neurotoxicity. In addition to stimulating NO production as effectively as LPS, zymosan also activates microglial PKC and associated non-NO-mediated neurotoxic pathways that may be important in human neurodegenerative diseases. Since the role of NO in human microglia-induced neurotoxicity is controversial, zymosan may prove more useful than LPS as a microglial activator in the rodent mixed neuronal/glial culture model.
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PMID:Role of protein kinase C in microglia-induced neurotoxicity in mesencephalic cultures. 905 44

Depletion of retinal dopamine in goldfish increases light sensitivity at photopic backgrounds. As horizontal cells appear not to be involved with this effect (Yazulla and Studholme [1995] Vis. Neurosci. 12:827-837), we investigated the innervation patterns of the ON rod/cone bipolar cells (ON-BC) by dopaminergic interplexiform cells (DA-IPCs) normally and during the period of neogeneration of new DA-IPCs at the marginal zone following DA-IPC destruction. DA-IPCs were destroyed via intraocular injection of 6-hydroxydopamine over 2 successive days. Controls and 1 year post-injection retinas were double labeled for protein kinase C and tyrosine hydroxylase (TH) immunocytochemistry to identify the ON-BCs and the DA-IPCs, respectively. Double-labeled 25 microns tissue sections were examined on a confocal laser scanning microscope by using dual channel immunofluorescence acquisition. Image stacks were analyzed for DA-IPC/ON-BC contacts in the distal inner nuclear layer (INL) and inner plexiform layer (IPL). Image stacks were rotated 180 degrees with respect to each other and reanalyzed to determine potential randomness of the contacts. For control retinas there were 1.8 contacts/axon terminal in the IPL (n = 165) and 9.4 contacts/ON-BC in the distal INL (n = 28). At 1 year after injection, reinnervation of TH-immunoreactive boutons in the retina recovered to 16% of control in the IPL but only 10% in the distal INL. Establishment of DA-IPC/ON-BC contacts recovered to 36% of control for ON-BC axon terminals (n = 103), whereas there was no recovery of contacts in the distal INL (n = 30). Reinnervation of ON-BC by DA-IPCs preferentially targets the axon terminals. The absence of reinnervation of bipolar cell dendrites by DA-IPCs may account for the persistence of the increased light sensitivity following retinal dopamine depletion. Thus, dopamine input to ON-BCs in the outer retina maybe involved in setting background sensitivity under photopic conditions.
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PMID:Differential reinnervation of retinal bipolar cell dendrites and axon terminals by dopamine interplexiform cells following dopamine depletion with 6-OHDA. 918 97

The protein kinases and protein phosphatases that act on tyrosine hydroxylase in vivo have not been established. Bovine adrenal chromaffin cells were permeabilized with digitonin and incubated with [gamma-32P]ATP, in the presence or absence of 10 microM Ca2+, 1 microM cyclic AMP, 1 microM phorbol dibutyrate, or various kinase or phosphatase inhibitors. Ca2+ increased the phosphorylation of Ser19 and Ser40. Cyclic AMP, and phorbol dibutyrate in the presence of Ca2+, increased the phosphorylation of only Ser40. Ser31 and Ser8 were not phosphorylated. The Ca2+-stimulated phosphorylation of Ser19 was incompletely reduced by inhibitors of calcium/calmodulin-stimulated protein kinase II (46% with KN93 and 68% with CaM-PKII 273-302), suggesting that another protein kinase(s) was contributing to the phosphorylation of this site. The Ca2+-stimulated phosphorylation of Ser40 was reduced by specific inhibitors of protein kinase A (56% with H89 and 38% with PKAi 5-22 amide) and protein kinase C (70% with Ro 31-8220 and 54% with PKCi 19-31), suggesting that protein kinases A and C contributed to most of the phosphorylation of this site. Results with okadaic acid and microcystin suggested that Ser19 and Ser40 were dephosphorylated by PP2A.
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PMID:Tyrosine hydroxylase phosphorylation in digitonin-permeabilized bovine adrenal chromaffin cells: the effect of protein kinase and phosphatase inhibitors on Ser19 and Ser40 phosphorylation. 937 70

Previous studies have demonstrated that the synergistic interaction of acidic fibroblast growth factor (aFGF) and a second co-activator molecule can novelly induce expression of the CA biosynthetic enzyme tyrosine hydroxylase (TH) in non-TH expressing neurons of the striatum. Several co-activators have been identified, including substances present in L6 muscle cell extract (X. Du et al., J. Neurosci. 14 (1994) 7688-7694) catecholamines, such as dopamine (DA) (X. Du and L. Iacovitti, J. Neurosci. 15 (1995) 5420-5427; X. Du et al., Brain Res. 680 (1995) 229-233) and activators of protein kinase C (PKC) such as TPA (X. Du and L. Iacovitti, J. Neurochem. 68 (1997) 564-569). In the present study, we investigated whether activators of the protein kinase A (PKA) pathway also serve as effective co-activators of aFGF in the induction of TH gene expression. In addition, the combinatorial effects of the various TH-inducing agents were also evaluated. We found that, as with other co-activating molecules, the PKA stimulants IBMX and forskolin had no TH-inducing capacity when administered alone. However, co-treatment of 10 ng/ml aFGF with either (250 microM) IBMX or (10 microM) forskolin resulted in the novel expression of TH in 25% of plated neurons. The number of TH-expressing neurons was increased to 55% in aFGF-treated cultures co-incubated with aFGF and both (250 microM) IBMX and (10 microM) forskolin. Time course studies indicated that TH induction was rapid (peaking within 24 h) and enduring (lasting 4 days in culture). Induction of TH by aFGF and IBMX/forskolin was partially blocked by inhibitors of protein kinase, such as H7, H8 and H89, as well as pretreatment with protein (cyclohexamide) or RNA synthesis (amanitin and actinomycin D) inhibitors. The concomitant addition of combinations of co-activator molecules (DA, TPA and IBMX/forskolin) and aFGF resulted in the additive induction of TH. Maximal expression of TH (80% of striatal neurons) was accomplished when cultures were treated with aFGF and all co-activator molecules simultaneously. Our results suggest that there are multiple ways to signal the initiation of the TH gene, each of which requires the synergy of specific growth factors and either DA, PKA or PKC pathway activators. Since only the combination of growth factor and all co-activators together produces maximum TH induction, each molecule may signal a unique intracellular pathway which converges at targets on the TH gene.
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PMID:Multiple signaling pathways direct the initiation of tyrosine hydroxylase gene expression in cultured brain neurons. 940 11

A single, large dose of N-methyl-D-aspartate (NMDA) or quisqualic acid (QA) injected into the chick eye has been shown previously to destroy many retinal amacrine cells and to induce excessive ocular growth accompanied by myopia. The purpose of this study was to identify distinct populations of retinal cells, particularly those believed to be involved in regulating ocular growth, that are sensitive to NMDA or QA. Two pmol of NMDA or 0.2 micromol of QA were injected unilaterally into eyes of 7-day-old chicks, and retinas were prepared for observation 1, 3, or 7 days later. Retinal neurons were identified by using immunocytochemistry, and cells containing fragmented DNA were identified by 3'-nick-end labelling in frozen sections. NMDA and QA destroyed many amacrine cells, including those immunoreactive for vasoactive intestinal polypeptide, Met-enkephalin, and choline acetyltransferase, but they had little effect upon tyrosine hydroxylase-immunoreactive cells. Other cells affected by both QA and NMDA included those immunoreactive for glutamic acid decarboxylase, gamma-aminobutyric acid, parvalbumin, serotonin, and aminohydroxy methylisoxazole propionic acid (AMPA) receptor subunits GluR1 and GluR2/3. Cells largely unaffected by QA or NMDA included bipolar cells immunoreactive for protein kinase C (alpha and beta isoforms) and amacrine cells immunoreactive for glucagon. DNA fragmentation was detected maximally in many amacrine cells and in some bipolar cells 1 day after exposure to QA or NMDA. We propose that excitotoxicity caused by QA and NMDA induces apoptosis in specific populations of amacrine cells and that these actions are responsible for the ocular growth-specific effects of QA and NMDA reported elsewhere.
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PMID:Immunocytochemical characterization of quisqualic acid- and N-methyl-D-aspartate-induced excitotoxicity in the retina of chicks. 952 96

The modulation of motor behavior by protein kinase C (PKC) signaling pathways in nigrostriatal neurons was examined by using a genetic intervention approach. Herpes simplex virus type 1 (HSV-1) vectors that encode a catalytic domain of rat PKCbetaII (PkcDelta) were developed. PkcDelta exhibited a constitutively active protein kinase activity with a substrate specificity similar to that of rat brain PKC. As demonstrated in cultured sympathetic neurons, PkcDelta caused a long-lasting, activation-dependent increase in neurotransmitter release. In the rat brain, microinjection of HSV-1 vectors that contain the tyrosine hydroxylase promoter targeted expression to dopaminergic nigrostriatal neurons. Expression of pkcDelta in a small percentage of nigrostriatal neurons (approximately 0.1-2%) was sufficient to produce a long-term (>/=1 month) change in apomorphine-induced rotational behavior. Nigrostriatal neurons were the only catecholaminergic neurons that contained PkcDelta, and the amount of rotational behavior was correlated with the number of affected nigrostriatal neurons. The change in apomorphine-induced rotational behavior was blocked by a dopamine receptor antagonist (fluphenazine). D2-like dopamine receptor density was increased in those regions of the striatum innervated by the affected nigrostriatal neurons. Therefore, this strategy enabled the demonstration that a PKC pathway or PKC pathways in nigrostriatal neurons modulate apomorphine-induced rotational behavior, and altered dopaminergic transmission from nigrostriatal neurons appears to be the affected neuronal physiology responsible for the change in rotational behavior.
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PMID:Modulation of rat rotational behavior by direct gene transfer of constitutively active protein kinase C into nigrostriatal neurons. 959 92


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