Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The exposure of the cephalic end of rats to repeated doses of X-irradiation (150 rad) immediately after birth induces a long-term increase in the noradrenaline (NA) content of cerebellum (CE) (+ 37.8%), and a decrease in cerebellar weight (65.2% of controls), which results in an increased NA concentration (+ 109%). This increase in the neurotransmitter level is accompanied by a dystonic syndrome and histological abnormalities: Purkinje cells (the target cells for NA afferents to CE) fail to arrange in a characteristic monolayer, and their primary dendritic tree appears randomly oriented. The injection of reserpine 0.9 and 1.2 mg/kg ip to adult rats for 18 h depletes cerebellar NA content in both controls (15.7 +/- 4 ng/CE and 2.8 +/- 1.5 ng/CE, respectively) and X-irradiated rats (17.1 +/- 1 ng/CE and 8.3 +/- 2 ng/CE, respectively). The activity of tyrosine hydroxylase (TH) in CE of adult rats, measured by an in vitro assay, is significantly increased in neonatally X-irradiated animals when compared to age-matched controls (16.4 +/- 1.4 vs 6.32 +/- 0.6 nmol CO2/h/mg prot., p less than 0.01). As observed for NA levels, a net increase in TH activity induced by the ionizing radiation is also measured: 308.9 +/- 23.8 vs 408.2 +/- 21.5 nmol CO2/h/CE, p less than 0.01 (controls and X-treated, respectively). These results suggest that X-irradiation at birth may induce an abnormal sprouting of noradrenergic afferents to CE. The possibility that these changes represent a response of the NA system to the dystonic syndrome is discussed.
Mol Chem Neuropathol
PMID:Increased activity of tyrosine hydroxylase in the cerebellum of the X-irradiated dystonic rat. 198 78

1. Earlier reports from this and other laboratories have indicated that wide variations exist in estimates of the concentrations of norepinephrine in the brain and heart of the snail Helix aspersa. This is a report on investigations of norepinephrine concentrations in Helix aspersa tissues using high-performance liquid chromatography with electrochemical detection. In addition, the effects of treatment with some amino acid precursors or enzyme inhibitors on the concentrations of norepinephrine, dopamine, 5-hydroxytryptamine, and some of their metabolites were investigated. 2. The levels of norepinephrine in the brain were low (46 ng/g) in comparison to dopamine (2.1) micrograms/g) and 5-hydroxytryptamine (2.6 micrograms/g). Epinephrine was not observed in either snail heart of snail nervous tissue. 3. Administration of L-3,4-dihydroxyphenylalanine resulted in elevated snail brain dopamine, while 3,4-dihydroxyphenylserine treatment increased norepinephrine. Treatment with blockers of tyrosine hydroxylase and aromatic-L-amino acid decarboxylase reduced dopamine concentrations without affecting 5-hydroxytryptamine. 4. The dopamine metabolite 3,4-dihydroxyphenylacetic acid was observed only after administration of L-3,4-dihydroxyphenylalanine or dopamine and then only in very small amounts. At no time was the dopamine metabolite homovanillic acid or the 5-hydroxytryptamine metabolite 5-hydroxyindoleacetic acid observed in brain, heart, or whole-body extracts of the snail. 5. Incubation of nervous tissue with either dopamine or 5-hydroxytryptamine resulted in the production of electrochemically active metabolites which were identified by oxidation characteristics and cochromatography with synthesized standards as the gamma-glutamyl conjugates of the amines. Treatment of snails with 5-hydroxytryptamine or dopamine also resulted in the production of gamma-glutamyl conjugates. 6. The present experiments show that great care must be exercised when measuring monoamines and their metabolites in gastropod tissues by high-performance liquid chromatography with electrochemical detection.
Cell Mol Neurobiol 1990 Jun
PMID:High-performance liquid chromatographic analysis of monoamines and some of their gamma-glutamyl conjugates produced by the brain and other tissues of Helix aspersa (Gastropoda). 211 17

The enzymatic activity of tyrosine hydroxylase (EC 1.14.16.2) increases in rat pheochromocytoma PC18 cells exposed to either elevated levels of cyclic AMP or glucocorticoids. The cyclic AMP-mediated increase in activity is elicited by cyclic AMP analogs or by compounds which activate adenylate cyclase or inhibit phosphodiesterase. The glucocorticoid-mediated increase is elicited only by glucocorticoid steroid hormones; nonglucocorticoid steroid hormones have no effect on tyrosine hydroxylase. In PC18 cells exposed simultaneously to both cyclic AMP-elevating agents and glucocorticoids, the increase in tyrosine hydroxylase activity is greater than that observed in cells treated with optimal concentrations of either inducing agent alone. Immunochemical titration experiments demonstrate that the increases in tyrosine hydroxylase activity observed in cells treated with the cyclic AMP analog, 8-bromocyclic AMP, and/or the synthetic glucocorticoid, dexamethasone, are due to increases in enzyme protein. Time course studies show that in cells treated with either 8-bromocyclic AMP or dexamethasone, the enzyme level increases slowly to a level 5-7-fold greater than that observed in untreated cells after 4 days of treatment. In cells treated with both of these inducing agents simultaneously, the enzyme level increases to a level 10-12-fold greater than that observed in control cells after 4 days of treatment. This additive increase in activity in cells treated with both inducing agents is observed at all time points. The rates of synthesis and degradation of tyrosine hydroxylase have also been measured in PC18 cells, using an antiserum to tyrosine hydroxylase to rapidly isolate radiolabeled enzyme from cells that have been incubated in the presence of [3H]leucine. The apparent half-life of tyrosine hydroxylase in the PC18 cells is approximately 30 hr. In PC18 cells incubated in the presence of radiolabeled leucine for 60 min, 0.2-0.3% of the total soluble protein synthesized is identified as tyrosine hydroxylase. In cells treated with either 8-bromocyclic AMP or dexamethasone for 24 hr, there is a 6-8-fold increase in the rate of synthesis of the enzyme. In cells treated with both inducing agents simultaneously, there is a 10-12-fold increase in the rate of synthesis; thus, the additive increase in enzyme level observed in cells treated with both inducing agents is paralleled by an additive increase in the rate of synthesis of the enzyme in these cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1986 Nov
PMID:Induction of tyrosine hydroxylase by cyclic AMP and glucocorticoids in a rat pheochromocytoma cell line: effect of the inducing agents alone or in combination on the enzyme levels and rate of synthesis of tyrosine hydroxylase. 243 Jan 69

In the rat, decreasing transsynaptic activity through adrenal denervation, nicotinic receptor blockade, or explanation is associated with an increase in preproenkephalin mRNA, enkephalin prohormone and peptide. In contrast, catecholamine pathways remain unchanged under similar conditions. Since it is not known whether changes in messenger RNA result from stabilization or increased synthesis, we exploited transcription 'run-on' assays to measure the rate of transmitter gene read out. Tyrosine hydroxylase message (TH-mRNA) was found to be the most abundantly produced transcript in the unmanipulated control rat adrenal medulla. TH-mRNA was produced in excess of twice the rate of transcription of the structural gene beta-actin. In contrast, preproenkephalin transcription occurred at a much lower rate (60% of the actin gene and only 25% of tyrosine hydroxylase gene transcription). All transcripts were inhibited by the polymerase II inhibitor, alpha-amanitin. After two days in explant culture, the rate of enkephalin transcription increased approximately 2-fold (to the same level as actin transcription); while tyrosine hydroxylase transcriptional activity fell to 30% of actin level. To analyze cellular mechanisms, explants were depolarized with potassium chloride. Enkephalin gene transcription was observed to be 2.5-fold less when grown under depolarizing conditions (50 mM KCl) than in control explants. On the other hand, tyrosine hydroxylase gene read-out was unchanged, similar to results obtained when TH catalytic activity was measured. These data indicate that membrane depolarization can selectively regulate expression of a transmitter gene product and are consistent with a proposed transsynaptic regulatory mechanism controlling biosynthesis of adrenal opiate peptides.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1989 Jan
PMID:Transcriptional control of adrenal catecholamine and opiate peptide transmitter genes. 256 22

Regulation of preprosomatostatin mRNA and tyrosine hydroxylase mRNA were examined in sympathetic neurons of the rat superior cervical ganglion (SCG). Surgical denervation of the adult SCG increased ganglion levels of preprosomatostatin (SS) mRNA more than 11-fold, and levels of the mRNA remained elevated 14 days after surgery. By contrast, denervation decreased levels of tyrosine hydroxylase (TH) mRNA. Potassium- or veratridine-induced membrane depolarization of cultured neonatal sympathetic neurons decreased levels of SS mRNA but elevated levels of TH mRNA. Sodium channel blockade with tetrodotoxin prevented the effects of veratridine on SS and TH mRNAs. In toto these observations suggest that transsynaptic nerve impulse activity and sympathetic neuron membrane depolarization decrease SS synthesis but increase TH synthesis at the mRNA level. Thus nerve impulse activity may alter the relative levels of different transmitters co-expressed in the same neuronal population by inhibiting levels of some species of mRNA while simultaneously stimulating levels of others.
Brain Res Mol Brain Res 1989 Jan
PMID:Differences in the effects of membrane depolarization on levels of preprosomatostatin mRNA and tyrosine hydroxylase mRNA in rat sympathetic neurons in vivo and in culture. 256 23

Long-term effects of lesions were analyzed in terms of gene expression. Nine months after unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (s. nigra), the remaining dopaminergic (DAergic) neurons (tyrosine hydroxylase (TH) cells determined by immunocytochemistry (ICC] on the lesioned side were atrophic with smaller nucleoli. By in situ hybridization, the DAergic neurons on the lesioned side had a 50% smaller TH-mRNA concentration than on the contralateral non-lesioned side. However, beta-tubulin mRNA concentration in DAergic neurons was unaffected by the lesion. The lesions did not alter TH-mRNA concentration in the contralateral non-lesioned side by comparison with unoperated controls. We propose that chronic lesions have long-term effects on gene expression because of damage sustained during compensatory hyperactivity after the lesion, or because of decreased trophic support from other neurons.
Brain Res Mol Brain Res 1989 May
PMID:Chronic lesions differentially decrease tyrosine hydroxylase messenger RNA in dopaminergic neurons of the substantia nigra. 256 83

In situ hybridization histochemistry was used to examine the development and regulation of tyrosine hydroxylase (TH) mRNA within the sexually dimorphic population of dopaminergic cells in the anteroventral periventricular nucleus (AVPv) of the hypothalamus. The AVPv contains over 3 times as many TH mRNA-containing cells in female rats, compared with males. This sexual dimorphism appears to be dependent on perinatal levels of gonadal steroids since orchidectomy of newborn males increased, and treatment of newborn females with testosterone decreased, the number of TH mRNA-containing cells detected within the AVPv. In addition, circulating gonadal steroids appear to downregulate TH expression within these cells in both adult male and female rats. In adult male animals, gonadectomy increased the number of TH mRNA cells in the AVPv within 7 days. Similarly, estradiol treatment prevented the increase in the number of TH mRNA-containing cells within the AVPv seen in ovariectomized female rats. No sexual differences were detected in the number of TH mRNA-containing cells within the suprachiasmatic preoptic nucleus, located just ventral to the AVPv. These findings indicate that perinatal gonadal steroids influence the number of cells within the AVPv that express TH in detectable amounts by determining the number of cells that are capable of producing sufficient quantities of TH message, as opposed to sex-specific alterations in the post-translational mechanisms. In the adult, circulating gonadal steroids appear to downregulate TH expression within these cells suggesting that testosterone and/or estrogen may exert a sustained influence on the biosynthetic activity of this sexually dimorphic population of dopaminergic cells.
Brain Res Mol Brain Res 1989 Dec
PMID:Hormonal control of the development and regulation of tyrosine hydroxylase expression within a sexually dimorphic population of dopaminergic cells in the hypothalamus. 257 4

Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, is subject to regulation by the cAMP as well as the calcium and cGMP second messenger systems. Treatment of intact rat PC12 cells with neuropeptides including secretin and vasoactive intestinal polypeptide (VIP) stimulated tyrosine hydroxylase activity 2 to 3-fold in vitro. Secretin (EC50 = 10 nM) was about 3 orders of magnitude more potent than VIP (EC50 = 3 microM). A combination of several protease inhibitors failed to enhance the potency of either peptide. Other members of the secretin family including glucagon and peptide histidine isoleucine (PHI) stimulated tyrosine hydroxylase activity to a lesser extent. Somatostatin, which is not homologous to secretin, was ineffective. The maximal response of tyrosine hydroxylase activation to 1 microM secretin occurred within 6-15 sec. Secretin, VIP, and forskolin also enhanced tyrosine hydroxylase activity (3,4-dihydroxyphenylalanine production) in intact cells, as determined by high performance liquid chromatography and electrochemical detection. Secretin, VIP, PHI, and glucagon increased the levels of cAMP in PC12 cells more than 10-fold, as determined by radioimmunoassay. We also demonstrated that cAMP is released from the cells into the incubation medium following secretin treatment. Secretin and VIP treatment also enhanced the activity of cAMP-dependent protein kinase in a concentration-dependent fashion, as measured subsequently in vitro. Based on the greater potency of secretin in comparison with VIP, PHI, and glucagon, we suggest that the PC12 cells contain a secretin-preferring receptor that increases cAMP levels and brings about an activation of tyrosine hydroxylase activity through the stimulation of cAMP-dependent protein kinase.
Mol Pharmacol 1989 Dec
PMID:Regulation of tyrosine hydroxylase activity in rat PC12 cells by neuropeptides of the secretin family. 257 21

The dopamine-producing neurons of the tuberoinfundibular region are known targets of estrogen and progesterone, and are of considerable neuroendocrine importance. To determine the anatomical distribution, and number of cells that contain tyrosine hydroxylase (TH) mRNA in the tuberoinfundibular region and other regions of the brain we carried out in situ hybridization on sections prepared from ovariectomized female rats given either oil vehicle, or estrogen, or estrogen plus progesterone. The intensity of label per cell was assessed to compare the relative amount of mRNA found per cell among TH-mRNA containing cells. [3H]cRNA probes to the rat TH sequence were used. Autoradiograms demonstrated the presence of TH-mRNA in the cytoplasm of cells in the arcuate and periventricular nuclei, zona incerta, substantia nigra, and the adrenal medulla. The number and anatomical distribution of cells that contained TH-mRNA was identical to the number and distribution of cells previously demonstrated by others to contain TH immunoreactivity. In the arcuate and periventricular nuclei, compared to treatment with estrogen alone, estrogen plus progesterone did lead to a statistically significant decrease in the number of TH mRNA-containing cells we could detect. No alteration in the mean number of grains per cell, among cells detected as containing TH-mRNA was found in any group. In contrast, these same hormone treatments had no effect on the number TH-mRNa producing cells we could detect in the zona incerta. Most of the cells in the zona incerta are found within the same tissue sections as arcuate/periventricular cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1989 Sep
PMID:Tyrosine hydroxylase mRNA in the neurons of the tuberoinfundibular region and zona incerta examined after gonadal steroid hormone treatment. 257 19

Cold stress is known to increase the synthesis and release of catecholamines in the sympathoadrenal system. Previously, we have demonstrated that cold exposure results in a 3- to 4-fold increase in adrenomedullary tyrosine hydroxylase (TH) activity, which is mediated by concomitant alterations in TH mRNA and protein levels. To further investigate the effects of stress on the expression of the catecholamine biosynthetic enzymes, we have isolated a rat cDNA clone encoding the epinephrine-synthesizing enzyme phenylethanolamine N-methyltransferase (PNMT). The cDNA clone is 905 nucleotides in length and contains a single open reading frame corresponding to 270 amino acids. The amino acid sequence predicted from this nearly full-length cDNA is 89% and 86% identical to that of bovine and human PNMT, respectively. Using the rat PNMT cDNA as a hybridization probe, we have measured the effects of cold stress on the relative abundance of adrenomedullary PNMT mRNA. Levels of PNMT protein were also estimated using an immunoblot analysis. As in the case of TH, cold exposure resulted in a rapid and prolonged increase in PNMT mRNA abundance, followed by concomitant increases in PNMT immunoreactivity. However, there appear to be quantitative and qualitative differences in the adaptive response of TH and PNMT to cold stress.
Brain Res Mol Brain Res 1989 Nov
PMID:Isolation of a rat adrenal cDNA clone encoding phenylethanolamine N-methyltransferase and cold-induced alterations in adrenal PNMT mRNA and protein. 257 95


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