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)

TT cell line is the best known stabilized cell line derived from the human medullary thyroid carcinoma. The ultrastructural characteristics of these cells include well developed rough endoplasmic reticulum, a prominent Golgi apparatus and a considerable number of secretory granules. Numerous hormones were immunocytochemically demonstrated in TT cells of which calcitonin and calcitonin gene-related peptide (CGRP) are the products of the same gene but an alternative RNA processing. TT cells were found to produce some other hormones as well, namely ACTH, neurotensin, enkephalin, PTHrP, gastrin-releasing peptide (GRP), serotonin but also functional proteins of the chromogranin group, synaptophysin, NSE, calbindin and tyrosine hydroxylase. Some marker proteins have been detected in the cytosol (CEA) and in the cytoskeleton (alpha-tubulin, cytokeratin). The influence of numerous factors on the secretory activity of these cells has been demonstrated so far, including effects of 1,25-dihydroxycholecalciferol, glucocorticoids, sex steroids, cAMP, gastrin-releasing peptide, sodium butyrate, phorbol esters, ionomycin and forskolin. The investigators performed on the TT cell line demonstrate that this is the most reliable model system for the human parafollicular cells developed so far, in comparison to other cell lines derived from the medullary carcinoma of the thyroid.
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PMID:Characterisation of thyroid medullary carcinoma TT cell line. 904 62

Primary cultures of gerbil mesencephalon were used for studying the modulation exerted by tachykinin NK(3) receptor activation on the activity of dopamine (DA) neurons. Dopamine neurons were identified by their ability to take up [(3)H]DA in a nomifensine-dependent manner. Moreover, tyrosine hydroxylase immunohistochemistry revealed that these neurons accounted for 5-7% of the total cell population. The NK(3) receptor agonists, senktide (EC(50) = 0.58 nM) and [MePhe(7)]neurokinin B (EC(50) = 3 nM), increased spontaneous [(3)H]DA release in a concentration-dependent manner. In contrast, tested at a supramaximal concentration (IC(50) = 0.89 nM), neither septide nor substance P were found to affect [(3)H]DA release. The senktide-evoked [(3)H]DA release was not observed when extracellular Ca(2+) was chelated, but was unaffected by nomifensine. This indicates that this increase in [(3)H]DA outflow resulted more from an exocytotic process than from reversal of carrier-mediated DA uptake. Moreover, the senktide effect was unaffected by the Na+ channel blocker tetrodotoxin, a result suggesting a direct action of senktide on DA neurons. The non-peptide NK(3) receptor antagonist, SR 142801, shifted or blocked (IC(50) = 0.89 nM) the senktide-evoked [(3)H]DA release, while its (-)-antipode, SR 142806, was 80-fold less potent, in agreement with binding data. Selective antagonists for Nk1 (SR 140333) or Nk2 (SR 48968) receptors failed to reduce the senktide effect. Light scanning microscopic analysis of mesencephalic cells loaded with the Ca(2+) sensitive dye, fluo-3, showed that senktide induced a rise in cytosolic Ca(2+) in 8-10% of the cell population. The senktide-induced elevation in intracellular Ca(2+) was rapid in onset and transient (at 10-8 M) or more sustained with no further increase in fluorescence intensity (at 10(-7) M). The proportion of senktide-responsive cells was not significantly modified when extracellular Ca(2+) was chelated, but was reduced by 87% in the presence of SR 142801 and by 75% in cultures that were pre-treated with the DA neurotoxin 1-methyl-4-phenylpyridinium. The present study shows that enhancement of spontaneous [(3)H]DA release and intracellular Ca(2+) mobilization may be observed after NK(3) receptor stimulation and that both biochemical events are likely to occur in DA neurons.
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PMID:Evidence for modulation of dopamine-neuronal function by tachykinin NK3 receptor stimulation in gerbil mesencephalic cell cultures. 908 31

Intracerebroventricular (IVT) administration of renin (R) to conscious male hydrated rats induces an increase in sodium excretion. The involvement of brain dopaminergic neurons in the renal action of IVT-R was investigated. Renin-induced natriuretic action was prevented by domperidone and by inhibition of tyrosine hydroxylase activity with alpha-methyl-p-tyrosine treatment. In addition, this effect was absent following selective central dopaminergic denervation with 6-hydroxydopamine (IVT) in combination with desmethylimipramine (IP). Our results suggest that renin acts centrally, at least in part, via an interaction with endogenous dopamine systems.
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PMID:Evidence for a dopaminergic involvement in the natriuretic action of centrally administered renin. 913 50

Oestrogens are the key factor in the sexual differentiation of the mammalian brain and play an important role in the activity of selected areas of the mature brain. To pursue the study of oestrogen action on neural cells at the molecular level, we developed a human neuroblastoma cell line (SK-ER3) expressing the oestrogen receptor (ER). Treatment of these cells with 17beta-oestradiol causes growth arrest and morphological and biochemical differentiation. The aim of the present study was to investigate whether oestrogen-differentiated SK-ER3 neuroblastoma cells acquire the ability to synthesize a specific neurotransmitter and whether the growth arrest previously reported can be ascribed to the blockage of the cells at a specific stage of the cell cycle. The results presented here indicate that oestrogens induce accumulation of SK-ER3 cells in the G0 phase of the cell cycle, underscoring the acquisition of a mature neural phenotype upon hormonal treatment. Most importantly, we show that in the differentiated cells the content of tyrosine hydroxylase and Na+-dependent dopamine uptake is significantly augmented, proving that the oestrogen-differentiated SK-ER3 cells can synthesize and store a specific neurotransmitter. In addition, we prove that the dopamine accumulated in differentiated SK-ER3 cells can be released. These studies therefore suggest that oestrogen treatment results in the acquisition of a fully functional dopaminergic phenotype of SK-ER3 cells. Ample evidence shows a link between dopaminergic neurons and oestrogen activity in hypothalamic and non-hypothalamic areas of the mammalian brain. Our study indicates that oestrogens might play a primary role in committing undifferentiated neuroblasts towards the dopaminergic phenotype.
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PMID:Dopaminergic phenotype induced by oestrogens in a human neuroblastoma cell line. 918 53

The norepinephrine transporter (NET) terminates noradrenergic neurotransmission at synapse by high-affinity sodium-dependent reuptake into presynaptic terminals, and thus serves as a marker of differentiation of noradrenergic neurons. In the present study, we studied the regulatory mechanism of the expression of NET-mRNA in cultured neurons from newborn rat superior cervical ganglia (SCG) and in clonal rat pheochromocytoma cells (PC12) SCG neurons in culture expressed a high level of NET-mRNA, which was further increased 2.5-5 fold from day 1 to day 13. Treatment of SCG neurons with the cholinergic differentiation factor (CDF)/leukemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF), neurokines known to induce the switch from adrenergic to cholinergic phenotype in SCG neurons, led to the suppression of the level of NET-mRNA in a concentration dependent manner, concomitantly with the suppression of mRNA for tyrosine hydroxylase (TH), an adrenergic marker enzyme in cultured SCG neurons. On the other hand, retinoic acid, a compound which is also known to increase the expression of choline acetyltransferase, a cholinergic marker enzyme, and suppress the expression of TH in the cultured SCG neurons and PCI2 cells, rather increased the level of NET-mRNA in these two cell populations. Alterations of the Na(+)-dependent norepinephrine transport activity which paralleled the changes in the NET-mRNA levels were confirmed by the [3H]norepinephrine uptake assay. These results indicate that cell extrinsic factors regulate the expressions of NET and TH genes by a common as well as by distinct mechanisms.
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PMID:Differential and coordinated regulation of expression of norepinephrine transporter in catecholaminergic cells in culture. 943 11

In the present study the renal response to intravenous infusion of the catecholamine precursors L-dihydroxyphenylalanine (L-DOPA) or L-tyrosine was investigated in thiopentone sodium-anaesthetized Sprague-Dawley rats. Glomerular filtration rate (GFR) was assessed by renal clearance of inulin, urinary concentration of dopamine (U(DA)V) by HPLC and sodium excretion (U(Na)V) by flame photometry. We found that basal U(DA)V was 6.5 +/- 0.5 pmol/min per 100 g body weight (mean +/- SEM). Intravenous infusion of L-tyrosine at 0. 1-3.0 micromol/min dose dependently enhanced U(DA)V (17 +/- 3 to 144 +/- 14 pmol/min respectively) with higher doses of L-tyrosine resulting in no further increase in U(DA)V. Compared with L-tyrosine administration significantly lower doses of L-DOPA (0.07 to 35 nmol/min) caused increases in U(DA)V which were orders of magnitude higher (18 +/- 1 to 7800 +/- 470 pmol/min, respectively) and did not show saturation characteristics. GFR did not change in response to L-tyrosine or L-DOPA infusion. No variations in urinary flow rate or in U(Na)V could be observed which were significantly correlated to changes in U(DA)V. In contrast, intravenous infusion of dopamine at a dose of 6 nmol/min significantly increased GFR by 35 +/- 6.2% and urinary flow rate by over 2-fold. Immunohistochemistry with light microscopy revealed no tyrosine hydroxylase in the kidney. Therefore, dopamine synthesis in the tubular cells mainly depends on the renal supply of L-DOPA. The unchanged GFR and U(Na)V in spite of large variations of U(DA)V argue against the hypothesis that intratubular dopamine plays a functional role in the regulation of hemodynamics or sodium transport in the kidney. Renal dopamine excretion may rather represent an effective pathway for the elimination of catecholamine precursors from the plasma.
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PMID:Renal response to infusion of dopamine precursors in anaesthetized rats. 945 71

Previous work has demonstrated that nitric oxide can be an important intracellular messenger in the regulation of neurosecretion in chromaffin cells. Since standard chromaffin cell cultures are mixed populations of noradrenaline and adrenaline producing cells, it would seem important to understand the functional differences between these individual components. The use of fluorescence imaging techniques for the recording of cytosolic calcium from single chromaffin cells together with the immunoidentification of individual cells with specific antibodies against tyrosine hydroxylase, N-phenyl ethanolamine methyl transferase and nitric oxide synthase, has allowed us to measure single-cell calcium responses in identified adrenergic, noradrenergic and nitrergic chromaffin cells, thus helping us to clarify the differential role of nitric oxide in the function of these chromaffin cell types. 53 +/- 2% of chromaffin cells were able to synthesize nitric oxide (nitric oxidesynthase-positive cells), these cells being mainly noradrenergic (82 +/-2%). Results indicate that nitric oxide donors such as sodium nitroprusside, molsidomine and isosorbide dinitrate evoke [Ca2+]i increases in a 62 +/- 4% of chromaffin cells, the response to nitric oxide donors being between 30 and 50% of that of 20 microM nicotine. Cells responding to nitric oxide donors were mainly adrenergic (68 +/- 5%) although 45 +/- 9% of noradrenergic cells also gave [Ca2+]i increasing responses. The distribution of nitric oxide responding cells between nitric oxide synthase-positive and negative was very similar in the whole population (63 +/- 5 and 60 +/- 7%, respectively), but these differences were more prominent when considering the distribution of nitric oxide response between noradrenergic and adrenergic nitric oxide synthase-positive cells; while 73 6% of adrenergic nitric oxide synthase-positive cells evoke [Ca2+]i increases by nitric oxide stimulation, only 35 +/- 11% of noradrenergic nitric oxide synthase-positive cells respond. Taken together these results seem to indicate that (i) nitric oxide could act within adrenal medulla as both an intracellular and intercellular messenger; and (ii) noradrenergic cells seem to be specialized in nitric oxide synthesis while adrenergic cells with an endocrine function could mainly act as a target of neurosecretory action of this second messenger.
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PMID:Segregation of nitric oxide synthase expression and calcium response to nitric oxide in adrenergic and noradrenergic bovine chromaffin cells. 946 16

This study was designed to evaluate whether the enzymes of the nitric oxide/cyclic-GMP pathway, nitric oxide synthase and soluble guanylyl cyclase, are functionally coupled in controlling catecholamine secretion in primary cultures of bovine chromaffin cells. In immunocytochemical studies, 80-85% of the tyrosine hydroxylase-positive chromaffin cells also possessed phenylethanolamine-N-methyltransferase, f1p4cating their capability to synthesize epinephrine. Immunoreactivity for neuronal-type nitric oxide synthase was found in over 90% of all chromaffin cells. Reverse transcription-polymerase chain reaction also demonstrated neuronal-type nitric oxide synthase messenger RNA. Immunoreactivity for soluble guanylyl cyclase was detectable in over 95% of chromaffin cells. Double-labeling immunofluorescence studies co-localized neuronal-type nitric oxide synthase and soluble guanylyl cyclase with tyrosine hydroxylase and phenylethanolamine-N-methyltransferase in the majority of chromaffin cells. Chromaffin cells possessed basal nitric oxide synthase activity which could be stimulated by acetylcholine and inhibited by NG-nitro-L-arginine methyl ester. Activation of soluble guanylyl cyclase by endogenously synthesized nitric oxide or the nitric oxide donor compound sodium nitroprusside was blocked by the inhibitor of soluble guanylyl cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Catecholamine release and the increase in cytosolic Ca2+ concentration evoked by acetylcholine were enhanced by inhibitors of the endogenous nitric oxide/cyclic-GMP pathway such as NG-nitro-L-arginine methyl ester, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one and the protein kinase G inhibitor Rp-8-pCPT-cGMPS. These data indicate that chromaffin cells possess an autocrine nitric oxide/cyclic-GMP pathway tonically controlling the inhibition of catecholamine release.
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PMID:Functional coupling of nitric oxide synthase and soluble guanylyl cyclase in controlling catecholamine secretion from bovine chromaffin cells. 948 18

The monoamines, serotonin, dopamine, norepinephrine, epinephrine and histamine, play a critical role in the function of the hypothalamic-pituitary-adrenal axis and in the integration of information in sensory, limbic, and motor systems. The primary mechanism for termination of monoaminergic neurotransmission is through reuptake of released neurotransmitter by Na+, CI-dependent plasma membrane transporters. A second family of transporters packages monoamines into synaptic and secretory vesicles by exchange of protons. Identification of those cells which express these two families of neurotransmitter transporters is an initial step in understanding what adaptive strategies cells expressing monoamine transporters use to establish the appropriate level of transport activity and thus attain the appropriate efficiency of monoamine storage and clearance. The most recent advances in this field have yielded several surprises about their function, cellular and subcellular localization, and regulation, suggesting that these molecules are not static and most likely are the most important determinants of extracellular levels of monoamines. Here, information on the localization of mRNAs for these transporters in rodent and human brain is summarized along with immunohistochemical information at the light and electron microscopic levels. Regulation of transporters at the mRNA level by manipulation in rodents and differences in transporter site densities by tomographic techniques as an index of regulation in human disease and addictive states are also reviewed. These studies have highlighted the presence of monoamine neurotransmitter transporters in neurons but not in glia in situ. The norepinephrine transporter is present in all cells which are both tyrosine hydroxylase (TH)- and dopamine beta-hydroxylase-positive but not in those cells which are TH- and phenyl-N-methyltransferase-positive, suggesting that epinephrine cells may have their own, unique transporter. In most dopaminergic cells, dopamine transporter mRNA completely overlaps with TH mRNA-positive neurons. However, there are areas in which there is a lack of one to one correspondence. The serotonin transporter (5-HTT) mRNA is found in all raphe nuclei and in the hypothalamic dorsomedial nucleus where the 5-HTT mRNA is dramatically reduced following immobilization stress. The vesicular monoamine transporter 2 (VMAT2) is present in all monoaminergic neurons including epinephrine- and histamine-synthesizing cells. Immunohistochemistry demonstrates that the plasma membrane transporters are present along axons, soma, and dendrites. Subcellular localization of DAT by electron microscopy suggests that these transporters are not at the synaptic density but are confined to perisynaptic areas, implying that dopamine diffuses away from the synapse and that contribution of diffusion to dopamine signalling may vary between brain regions. Interestingly, the presence of VMAT2 in vesicles underlying dendrites, axons, and soma suggests that monoamines may be released at these cellular domains. An understanding of the regulation of transporter function may have important therapeutic consequences for neuroendocrine function in stress and psychiatric disorders.
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PMID:Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system. 966 36

Administration of high doses of glutamate (Glu) leads to selective neurodegeneration in discrete brain regions near circumventriclular organs of the early postnatal mouse. The arcuate nucleus-median eminence complex (ARC-ME) appears to be the most Glu-sensitive of these brain regions, perhaps because of the intimate relationships between its neurons and specialized astroglial tanycytes. To investigate the mechanism of Glu-induced neuronal loss, we administered graded doses of the sodium salt of glutamate (MSG) to postnatal mice, measured their plasma Glu concentrations, and performed microscopic analyses of the ARC-ME region 5 h after treatment. Nursing, 7-day-old mouse pups (CD1, Charles River, Hollister, Calif.) were injected subcutaneously with single doses of 0.1-0.5 or 1.0-4.0 mg of MSG per g BW, or with water vehicle alone. Mice were decapitated 5 h later and the brains immediately fixed by immersion in buffered aldehydes. Frontal vibratome tissue sections at comparable levels of the ARC-ME were examined by light microscopy. A dose of 4.0 mg MSG/g BW caused neurodegeneration throughout the ARC region, while 1.0 mg/g MSG resulted in less extensive damage. Injection of 0.2 mg MSG/g BW, which raised plasma Glu concentrations 17-fold after 15 min, was the minimum dose tested at which nuclear and cytoplasmic changes were observed in a small group of subependymal neurons near the lateral recesses of the third ventricle. Higher doses of 0.3-0.5 mg MSG caused injury to additional neurons situated farther laterally, but damage remained confined to the ventral region of the ARC nucleus. Ultrastructural examination showed some subependymal neurons with pyknotic nuclei, reduced cytoplasmic volume, and swollen subcellular organelles, while others had fragmented and condensed nuclear material. Immunostaining for tyrosine hydroxylase indicated that dopamine neurons were spared at the threshold dose, but suffered damage after higher doses of MSG. Immunostaining for Glu receptor subtypes revealed that 0.2 mg MSG/g BW enhanced neuronal expression of NMDAR1 and of GluR2/4, and that higher doses of MSG preferentially increased NMDAR1 expression in injured neurons. These results extend previous reports of Glu sensitivity in the ARC-ME region of 7-day postnatal mice. A dose of 0.2 mg MSG/g BW s.c. causes clear but discrete injury to specific subependymal neurons of undetermined phenotype near the base of the third ventricle. Slightly higher doses of MSG evoke damage of additional neurons confined to the ventral region of the ARC traversed by tanycytes. These same greater amounts of MSG promote dose-related increase in the expression of NMDAR1 more than of GluR2/4 in injured ARC neurons, suggesting that elevated Glu receptor levels may contribute to or be related to neuronal cell death. Taken together with previous findings, the data suggest that Glu responsitivity in the ARC-ME of the postnatal mouse may result from transient developmental conditions involving the numerical ratios and juxtaposition between tanycytes and neurons, expression of Glu receptors, and perhaps other ontogenetic factors which may not persist in the mature adult.
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PMID:Exogenous glutamate enhances glutamate receptor subunit expression during selective neuronal injury in the ventral arcuate nucleus of postnatal mice. 970 74


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