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

1. The influence of some drugs which affect the dopaminergic system was studied on chemosensory responses to dopamine (DA), acetylcholine (ACh), sodium cyanide NaCN) and hypoxia during experiments on pentobarbitone anaesthetized cats in which chemoreceptor activity was recorded from the peripheral end of a sectioned sinus nerve. 2. Spontaneous chemosensory activity was inhibited in a dose-dependent manner by DA (0.5-5 microgram, I.A.). Higher doses (10-50 microgram) caused a delayed increase in discharge and were associated with inconsistent inhibitory responses. 3. The DA antagonist alpha-flupenthixol (0.2 mg/kg, I.A.) blocked the inhibitory response to DA without affecting either the spontaneous discharge frequency or the response to ACh. The effect of NaCN was potentiated, and during hypoxia chemoreceptor activity increased more rapidly, although the maximum frequency attained was not appreciably different from control values. Similar results were obtained with haloperidol (0.5 and 1.0 mg/kg, I.V.). 4. Higher doses of alpha-flupenthixol (0.5-1.0 mg/kg, I.A.) increased spontaneous chemoreceptor activity, but this was regarded as a non-specific effect of the drug since at these doses the inhibitory effect of 5-hydroxytryptamine (5-HT) was also abolished. 5. The animals were exposed to alternate periods of hypoxia and hyperoxia following administration of the tyrosine hydroxylase inhibitor alpha-methyl p-tyrosine (AMPT, 0.2-10 mg/kg, I.A.). The inhibitory response previously evoked by amphetamine was abolished, and electron microscopic studies showed a great reduction in the number of dense-cored granules, both of which suggested that DA levels in the carotid body had been substantially reduced. Responses to NaCN and hypoxia were slightly potentiated following AMPT, but neither spontaneous activity nor the response to ACh was affected. 6. Apomorphine (0.05-0.2 mg/kg, I.A.) inhibited the chemoreceptor discharge for up to 45 min, an effect which was antagonized by alpha-flupenthixol (0.2 mg/kg, I.A.), implying it resulted from DA receptor stimulation. Although responses to NaCN, hypoxia and higher doses of ACh were reduced following administration of apomorphine, the reduction was not very marked. 7. These results are not compatible with the theory of Osborne & Butler (1975), that in normoxia DA is tonically released in the carotid body and suppresses spontaneous chemosensory activity. 8. It is concluded that DA modulates chemosensory activity by influencing the rate of increase in discharge, without affecting maximum discharge frequency. The mechanism whereby DA is released in response to increased chemosensory activity remains to be established.
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PMID:Inhibitory action of dopamine on cat carotid chemoreceptors. 67 58

The protonophores carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and carbonyl cyanide m-chlorophenylhydrazone (CCCP) stimulated the synthesis of 14C-catecholamines from [14C]tyrosine in cultured bovine adrenal medullary cells. The stimulatory effect of CCCP but not of FCCP was partially dependent on extracellular Ca2+. CCCP but not FCCP increased the influx of 45Ca2+ to the cells. When cells were incubated with either CCCP or FCCP (0.01-0.2 microgram/ml), the intracellular pH fell from 7.2 to 6.3-6.5 and catecholamine synthesis increased. Tyrosine hydroxylase activity in a soluble fraction prepared from cultured adrenal medullary cells was measured after incubation of the cells with FCCP or CCCP. Although FCCP did not affect the activity of the enzyme, CCCP caused a stable activation of it which was dependent on extracellular Ca2+. Since the optimal pH of soluble tyrosine hydroxylase is around 6.0 in adrenal medullary cells, FCCP may increase the synthesis of catecholamines by shifting the intracellular pH toward it. In addition to this mechanism, CCCP may enhance the synthesis of catecholamines by a Ca2+-dependent mechanism.
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PMID:Effects of protonophores on the synthesis of catecholamines and the intracellular pH in cultured bovine adrenal medullary cells. 289 5

A population of cells in the anterior substantia nigra pars compacta (SNPc) of the guinea-pig have been reported previously that differ from classical dopaminergic neurons in terms of their active and passive membrane properties. To investigate this population further, anterior nigral neurons (n = 17) were compared with neurons in the adjacent subthalamic nucleus (STN: n = 26). The anterior nigral neurons were found to be indistinguishable from STN neurons in their action potential characteristics, firing rate, resting membrane potential and input resistance. A low-threshold calcium conductance and anomalous rectification could be demonstrated in cells from both groups. Furthermore, the gross morphological characteristics of anterior nigral neurons and STN neurons were very similar, as assessed following the intracellular injection of biocytin. A further similarity was seen in the response of the two cell groups to cyanide (200 microM) and apomorphine (500 microM). Cyanide hyperpolarised the membrane potential of all STN neurons and the majority (77.8%) of anterior nigral neurons, in both cases producing a concomitant reduction in firing rate. These changes were accompanied by an increase in membrane conductance for potassium ions. Apomorphine depolarised the membrane potential of all STN neurons and anterior nigral neurons, in most cases increasing the input resistance (83.3% of STN neurons and 100% of anterior nigral neurons). In both groups of cells, when firing rate was affected, an increase was usually seen. Given the physiological, morphological and pharmacological similarities of STN and anterior nigral neurons, the most parsimonious interpretation is that the anterior nigral neurons belong to the STN. However, the anterior nigral neurons were found in slices that, when resectioned, contained tyrosine hydroxylase (TH)-immunoreactive cell bodies in every section, in a location corresponding to the SNPc. The implication is that in the guinea pig the SNPc and STN (usually considered to be anatomically distinct nuclei) intermix at this level for several hundred microns. This close association of the STN and the compacta was further demonstrated by the presence of TH-positive varicose and non-varicose neuronal processes within the STN.
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PMID:Possible intermixing of neurons from the subthalamic nucleus and substantia nigra pars compacta in the guinea-pig. 877 36

In rat brain substantia nigra catecholamine neurons in vitro, a sensitive indicator of excitatory amino-acid-induced damage is dendritic degeneration that precedes the loss of the cell body. The present study has shown that dendritic loss is not specific for excitatory amino acids and is an early indicator of neurodegeneration produced by numerous agents that initiate damage by different primary cellular actions. Rats were anesthetised by fluothane inhalation and killed, and the brain was rapidly removed. Three-hundred-micrometer-thick slices containing substantia nigra were incubated for 2 h at 35 degrees C in the presence or absence of kainic acid (50 microM), 1-methyl-4-phenylpyridinium ion (10 or 50 microM), ouabain (10 or 30 microM), 6-hydroxydopamine (10 or 100 microM), potassium cyanide (100 microM or 1 mM), or elevated extracellular potassium chloride (25, 50, or 100 mM). The slices were fixed and recut into thin sections (30 micrometer) and substantia nigra dopamine neurons were immunolabeled for tyrosine hydroxylase coupled to diaminobenzidine. Both the cell body and the extensive dendritic projections were immunolabeled. Each agent caused a similar pattern of toxicity including loss of tyrosine-hydroxylase-immunolabeled dendrites at lower concentrations and damage to, or disintegration of, the cell bodies at higher concentrations. For example, 100 microM potassium cyanide reduced the proportion of substantia nigra neurons which exhibited dendrites from 66 +/- 4% (SEM) in controls to 54 +/- 7%, without obvious changes in cell bodies. After 1 mM potassium cyanide, only 13 +/- 2% of substantia nigra neurons retained dendrites and cell bodies were shrunken or disintegrated. Loss of dendrites was also evident in substantia nigra neurons stained with cresyl violet or immunolabeled for microtubule-associated protein 2. The findings suggest that disruption of the dendritic arbor is an early indicator of neurodegeneration, irrespective of how this is initiated. The approach that we have developed may therefore prove valuable in investigating the mechanisms of degeneration of catecholamine neurons.
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PMID:Dendrite loss is a characteristic early indicator of toxin-induced neurodegeneration in rat midbrain slices. 1068 96

Adaptation to hypoxia is a topic of considerable clinical relevance, as it influences the pathophysiology of anaemia, polycythaemia, tissue ischaemia and cancer. A growing number of physiologically relevant genes are regulated in response to changes in intracellular oxygen tension. These include genes encoding erythropoietin, vascular endothelial growth factor and tyrosine hydroxylase. Studies on the regulation of the erythropoietin gene have provided insights into the common mechanism of oxygen sensing and signal transduction, leading to activation of the hypoxia-inducible transcription factor 1 (HIF-1). Activation of HIF-1 by hypoxia depends on rescue of its alpha-subunit from oxygen-dependent degradation in the proteasome, allowing it to form a heterodimer with HIF-1 beta. This then translocates to the nucleus. There, HIF-1 assembles with a highly conserved orphan nuclear receptor, HNF-4, and a critical transcriptional adaptor, p300. This complex binds to a 3' enhancer on the erythropoietin gene, enabling transcription of erythropoietin. HIF-1 also activates other genes, the cis-acting elements of which contain cognate hypoxia response elements. There is growing evidence that the oxygen sensor is a flavohaem protein and that the signal transduction pathway involves changes in the level of intracellular reactive oxygen intermediates. We have recently cloned a novel fusion protein called cytochrome b5/b5 reductase, which is a cyanide-insensitive NADPH oxidase and, therefore, a candidate to be the oxygen sensor. This flavohaem protein is widely expressed in cell lines and tissues, with localization in the perinuclear space. In the presence of oxygen and iron, it may induce oxidative modifications that target HIF-1 alpha for ubiquitination and degradation.
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PMID:Detecting and responding to hypoxia. 1181 5

We have previously shown that the membrane-associated form of the GABA-synthesizing enzyme, glutamate decarboxylase 65 (GAD(65)), is activated by synaptic vesicle proton gradient-mediated protein phosphorylation. We now report that the rate-limiting enzyme in dopamine (DA) biosynthesis, tyrosine hydroxylase (TH), is regulated similarly to GAD(65). The membrane-associated form of TH (MTH) was activated by conditions favoring protein phosphorylation (e.g. ATP) and was inhibited by phosphatase (e.g. calf intestine phosphatase). Furthermore, the ATP-mediated activation of MTH was abolished by conditions that disrupted the proton gradient of synaptic vesicles, e.g. the presence of carbonyl cyanide M-chorophenylhydrazone, gramicidin, or the V-type ATPase inhibitor (bafilomycin), but not the P-type ATPase inhibitor (vanadate). Moreover, DA newly synthesized from tyrosine by MTH and membrane-associated aromatic amino acid decarboxylase was taken up preferentially rather than pre-existing DA. Therefore, the previously proposed model showing close coupling between GABA synthesis and GABA packaging into synaptic vesicles by vesicular GABA transporters is also applicable to the DA system. Hence, it is concluded that there is a general coupling mechanism between neurotransmitter synthesis and packaging of transmitter into synaptic vesicles.
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PMID:Demonstration of functional coupling between dopamine synthesis and its packaging into synaptic vesicles. 1463 Nov 17

This study investigated the neuroprotective effect of somatostatin, cortistatin and agonists at somatostatin(2) (sst(2)) receptors in retinal explants subjected to chemical ischaemia. Eyecups of female Sprague-Dawley rats (250-300 g) were immersed in PBS buffer or PBS containing iodoacetic acid (IAA; 0.5, 5, 50, 100 mM) and sodium cyanide (NaCN; 2.5, 25, 250, 500 mM) (chemical ischaemia solution) for 15, 30, 45, 60, 120 min (pilot study). Subsequently, eyecups were incubated with (1) PBS, (2) chemical ischaemia solution (5 mM IAA/25 mM NaCN) or (3) somatostatin, cortistatin, BIM23014 or MK678 (0.1, 1, 10 microM) together with the chemical ischaemia solution for 60 min, followed by a second 60-min incubation in PBS (control and ischaemia groups) or ligands in PBS (neuroprotection groups). The eyecups were subsequently fixed and sectioned for immunohistochemistry. Treatment of the eyecups with IAA/NaCN (5/25 mM) for 60 min abolished choline acetyltransferase (ChAT), tyrosine hydroxylase and brain nitric oxide synthase immunoreactivity in the inner nuclear, inner plexiform and ganglion cell layers. It also abolished protein kinase C immunoreactivity in rod bipolar cells and terminals, but did not damage ganglion cells labelled for microtubule-associated protein-1. TUNEL staining provided evidence of cell death in the ischaemic retina. Cortistatin, BIM23014 and MK678 attenuated the retinal damage caused by the chemical ischaemia in a concentration dependent manner. The ligands afforded approximately 58, 76 and 49% neuroprotection, respectively, of the ChAT immunoreactive cells. These results demonstrate that somatostatin analogues can protect the retina from ischaemic damage. The chemical ischaemia model is presently employed for the elucidation of the mechanisms involved in the neuroprotection.
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PMID:Effect of somatostatin analogues on chemically induced ischaemia in the rat retina. 1564 93

Hypoxia-inducible factor 1 (HIF-1) is a critical mediator of physiological responses to acute and chronic hypoxia. First, HIF-1 is required for the development of the systems that mediate these responses, including the heart, blood and blood vessels. Mice with complete HIF-1alpha deficiency manifest developmental defects that involve all three components of the circulatory system. Second, HIF-1 mediates changes in gene expression that underlie physiological responses to chronic hypoxia, such as increased erythropoiesis and angiogenesis. Hif1a(+/-) mice, which are partially HIF-1alpha deficient, manifest impaired hypoxia-induced pulmonary vascular remodelling. Smooth muscle cells from pulmonary arteries (PASMCs) of wild-type mice subjected to chronic hypoxia manifest hypertrophy, depolarization, increased [Ca2+]i, and decreased voltage-gated K+ currents. These responses are impaired in PASMCs from Hif1a(+/-) mice. Carotid bodies isolated from Hif1a(+/-) mice are unresponsive to hypoxia despite normal histology and normal responses to cyanide stimulation. Rat PC12 cells share properties with O2-sensing glomus cells of the carotid body, including hypoxia-inducible expression of tyrosine hydroxylase, the rate limiting enzyme for catecholamine biosynthesis. In PC12 cells subjected to intermittent hypoxia, Ca2+/calmodulin-dependent kinase activity leads to HIF-1 transcriptional activity and tyrosine hydroxylase mRNA expression. Thus, HIF-1 regulates both acute and chronic responses to continuous and intermittent hypoxia.
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PMID:Regulation of gene expression by HIF-1. 1668 26

Previous studies have demonstrated a deficiency in mitochondrial function in Parkinson's disease. We measured the ability of mitochondrial inhibitors of complexes I (rotenone, MPP(+), and HPP(+)), II (amdro), IV (Na cyanide), and an uncoupler (dinoseb) to release preloaded dopamine from murine striatal synaptosomes. These compounds were potent dopamine releasers, and the effect was calcium-dependent. The striatum also contains a significant density of K(ATP)(+) channels, which play a protective role during ATP decline. Blockage of these channels with glibenclamide only potentiated the dopamine release by complex I inhibitors, and a selective potentiating effect of glibenclamide on the toxicity of MPTP was also observed, in vivo, using C57BL/6 mice. Western blots of striatal dopamine transporter (DAT) and tyrosine hydroxylase (TH) proteins demonstrated that 30 mg/kg of glibenclamide alone did not affect the expression of DAT and TH after two weeks of daily treatments, but it significantly enhanced the reduction of DAT and TH by a single dose of 20 mg/kg of MPTP. Amdro or dinoseb alone, or in conjunction with glibenclamide did not alter the expression of DAT and TH. The possible mechanisms underlying dopamine release and the selectivity of glibenclamide were further evaluated, in vitro. (86)Rb efflux assay showed that glibenclamide inhibited rotenone-induced K(+) efflux, but not dinoseb-induced K(+) efflux. Analysis of ATP titers in treated synaptosomes did not support a correlation between mitochondrial inhibition and K(ATP)(+) channel activation. However, assay of reactive oxygen species (ROS) showed that greater amounts of ROS generated by complex I inhibitors was a contributory factor to K(ATP)(+) channel activation and glibenclamide potentiation. Overall, these findings suggest that co-exposure to mitochondrial complex I inhibitors and glibenclamide or a genetic defect in K(ATP)(+) channel function, may increase neurotoxicity in the striatal dopaminergic system.
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PMID:Potentiating effect of the ATP-sensitive potassium channel blocker glibenclamide on complex I inhibitor neurotoxicity in vitro and in vivo. 1672 3

Cyanide is a potent neurotoxicant that can produce dopaminergic neuronal death in the substantia nigra and is associated with a Parkinson-like syndrome. In this study involvement of Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3), a BH3-only Bcl-2 protein, in cyanide-induced death of dopaminergic cells was determined in mice and Mes 23.5 cells. Treatment of mice with cyanide up-regulated BNIP3 and Bax expression in tyrosine hydroxylase (TH)-positive cells of the substantia nigra, and progressive loss of TH-positive neurons was observed over a 9-day period. In Mes 23.5 dopaminergic cells, cyanide stimulated translocalization of BNIP3 to both endoplasmic reticulum (ER) and mitochondria. In ER, BNIP3 stimulated release of Ca(2+) into the cytosol, followed by accumulation of mitochondrial Ca(2+), resulting in reduction of mitochondrial membrane potential (Deltapsi(m)) and eventually cell death. Cyanide also activated Bax to colocalize with BNIP3 in ER and mitochondria. Forced overexpression of BNIP3 activated Bax, whereas gene silencing reduced Bax activity. Knockdown of Bax expression by small interfering RNA blocked the BNIP3-mediated changes in ER and mitochondrial Ca(2+) to block cyanide-induced mitochondrial dysfunction and cell death. These findings show that BNIP3-mediates cyanide-induced dopaminergic cell death through a Bax downstream signal that mobilizes ER Ca(2+) stores, followed by mitochondrial Ca(2+) overload.
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PMID:Cyanide-induced apoptosis of dopaminergic cells is promoted by BNIP3 and Bax modulation of endoplasmic reticulum-mitochondrial Ca2+ levels. 1984 71


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