Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Catecholamine neurotransmitters--dopamine, noradrenaline (norepinephrine), adrenaline (epinephrine)--are synthesized in catecholaminergic neurons from tyrosine, via dopa, dopamine and noradrenaline, to adrenaline. Four enzymes are involved in the biosynthesis of adrenaline: (1) tyrosine 3-mono-oxygenase (tyrosine hydroxylase, TH); (2) aromatic L-amino acid decarboxylase (AADC, or DOPA decarboxylase, DDC); (3) dopamine beta-mono-oxygenase (dopamine beta-hydroxylase, DBH); and (4) noradrenaline N-methyltransferase (phenylethanolamine N-methyltransferase, PNMT). We cloned full-length complementary DNAs (cDNAs) and genomic DNAs of human catecholamine-synthesizing enzymes (TH, AADC, DBH, PNMT) and determined the nucleotide sequences and the deduced amino acid sequences. We discovered multiple messenger RNAs (mRNAs) of human TH, human DBH, and human PNMT. Four types (types 1, 2, 3, and 4) of human TH mRNAs are produced by alternative mRNA splicing mechanism from a single gene. We found the multiple forms of TH in two species of monkeys, but only a single mRNA corresponding to human TH type 1 in Sunkus murinus and rat, suggesting that the multiplicity of TH mRNA is primate-specific. Total TH mRNA, especially the most abundant type 2 and type 1 mRNAs in the human brain, were found to be reduced during the process of aging. The multiple forms of human TH may give additional regulation to the human enzyme, probably through altered phosphorylation and activation. We have succeeded in producing transgenic mice carrying multiple copies of the human TH gene in brain and adrenal medulla. The level of human TH mRNA in brain was about 50-fold higher than that of endogenous mouse TH mRNA. In situ hybridization demonstrated an enormous region-specific expression of the transgene in substantia nigra and ventral tegmental area. TH immunoreactivity in these regions, Western blot analysis, and TH activity measurements proved definitely increased TH in transgenic mice, though not comparable to the increment of the mRNA. However, catecholamine levels in transgenics were not significantly different from those in non-transgenics. The results suggest complex regulatory mechanisms for human TH gene expression and for the catecholamine levels in transgenic mice. Kohsaka and Uchida in collaboration with us applied genetically engineered (human TH cDNA-transfected) non-neuronal cells to brain tissue transplantation in parkinsonian rat models. We isolated and sequenced a full-length cDNA encoding human AADC.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Genes for human catecholamine-synthesizing enzymes. 168 50

In situ hybridization and Northern blot analysis has been used to analyse in some detail the localization and regulation of the messenger molecules adrenaline, noradrenaline and neuropeptide tyrosine (NPY) within cells of the sympathetic nervous system and the adrenal medulla. In the rat adrenal gland, a novel NPY containing population of ganglion cells was found. Synthetic oligonucleotide probes complementary to mRNA coding for the catecholamine synthesizing enzymes phenylethanolamine N-methyltransferase (PNMT), tyrosine hydroxylase (TH) and NPY were used to analyse the regulation of these genes following administration of the catecholamine depleting drug reserpine. Twenty-four hours after a single dose of reserpine, a differential regulation of PNMT, TH and NPY was found. Thus, a dramatic decrease in PNMT mRNA was observed in the adrenal medulla. In contrast, mRNA for both TH and NPY exhibited an increase. Different regulatory mechanisms may thus operate for these three compounds coexisting in chromaffin cells of the adrenal medulla. The regulation of enzymes and peptides was also studied in human sympathetic ganglia. After brief electrical preganglionic stimulation of thoracic ganglia in humans, in situ hybridization was performed with synthetic oligonucleotide probes complementary to TH, dopamine beta-hydroxylase (DBH) and NPY mRNA respectively. A several fold increase in all three mRNAs was found in the principal ganglion cells. The results point to a very rapid regulation of genes involved in signal transmission in the sympathetic nervous system of humans. The results also suggest a novel way to define neuronal projections by visualizing increases in mRNA levels following electrical stimulation.
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PMID:Colocalization of neurotransmitters analyzed by in situ hybridization. 168 76

Primary cultures of chromaffin cells were prepared from bovine adrenal medullae and the levels of mRNA for tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) determined. The cells expressed moderate levels of TH mRNA and low levels of PNMT mRNA. The latter appeared to be more sensitive than TH mRNA to variations in the culture medium. The treatment of cultures with agents that activate signal transduction pathways, forskolin or phorbol esters, dramatically enhanced the expression of both mRNAs. The forskolin-induced increases in the steady-state levels of TH and PNMT mRNAs occurred rapidly and were apparent within 5 hours. These data suggest that the TH and PNMT genes can be regulated by second messengers. In contrast, dexamethasone treatment dramatically increased PNMT mRNA with no change in TH mRNA. The increase in PNMT mRNA was apparent within 6 hours of addition of the drug to the culture medium.
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PMID:Differential and coordinate regulation of TH and PNMT mRNAs in chromaffin cell cultures by second messenger system activation and steroid treatment. 172 44

The present study compared the activities of some of the monoamine synthesizing enzymes in several brain regions, the retina as well as adrenal gland of albino Sprague-Dawley (SD) and Long-Evans hooded (LE) rats. Brainstem, hypothalamic and retinal tyrosine hydroxylase (TH) activity were significantly higher in LE than in SD. In addition to higher enzyme activity, a larger number of TH-immunoreactive perikarya as well as a higher concentration of TH-immunoreactive processes were observed in the retina of LE rats. There was no strain difference in TH activity of caudate nucleus (CN) and substantia nigra (SN). In contrast to brain regions and retina, adrenal TH activity was markedly higher in SD than in LE animals. Aromatic L-amino acid decarboxylase (AADC) activity of both the brainstem and adrenal gland in the LE strain was lower than in SD animals. No differences in the AADC activity of hypothalamus, SN and CN were found between LE and SD strains. Phenylethanolamine N-methyltransferase (PNMT) activity of the hypothalamus, retina and adrenal gland of LE strains was significantly lower than in SD rats. In spite of the difference in the enzyme activity, there were no marked morphological changes observed in PNMT-immunostaining patterns between the retina of LE and SD rats. Tryptophan hydroxylase activity of both the brainstem and hypothalamus did not exhibit strain differences.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Strain differences between albino and pigmented rats in monoamine-synthesizing enzyme activities of brain, retina and adrenal gland. 196 57

The purpose of this study was to examine the effects of angiotensin on the enzyme activities and gene expression of two catecholamine synthesizing enzymes, tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT), in bovine adrenal medullary (AM) cells. Short term (15 min) incubation of cultured AM cells with 2 nM [Sar1]angiotensin II (s1-AII) did not increase basal secretion of catecholamines; however, longer incubations (3, 24, or 72 h) produced 4-10-fold increases. To determine whether angiotensin affects synthesis of catecholamines, the activities of TH and PNMT were examined. Incubation with s1-AII (15-30 min) decreased the Km of TH for its biopterine cofactor [6R)-5,6,7,8-tetrahydro-1-biopterin dihydrochloride (BH4] without affecting the Vmax, suggesting activation of TH. After long term incubation (72 h) the Km value was identical to that of control, while increases in the apparent Vmax were observed. PNMT activity was unaffected during a 30-min treatment with s1-AII; however, 2-fold increases occurred after a 48-72-h incubation. s1-AII (24 h) increased the relative abundance of TH and PNMT mRNAs, suggesting that the long term increase in enzyme activities reflected increased expression of TH and PNMT genes. Maximal increases were observed at 2 nM s1-AII and the changes were antagonized by saralasin. Induction of TH mRNA by s1-AII was additive to the effects of veratridine or forskolin indicating that effects of angiotensin were not due to membrane depolarization or increased cyclic AMP levels. Incubation with Ca2+ ionophore A23187 increased TH and PNMT mRNA levels in AM cells raising the possibility that the increase in cellular [Ca2+] could mediate effects of angiotensin. Angiotensin-induced increases in TH and PNMT mRNA were inhibited by nifedipine indicating involvement of voltage-dependent Ca2+ channels. In addition, the increases in TH, but not PNMT mRNA, were antagonized by dantrolene, which inhibits mobilization of Ca2+ from intracellular stores. Calmodulin involvement was suggested by the inhibition of s1-AII induced changes in mRNA with 1 microM calmidazolium.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Short and long term regulation of catecholamine biosynthetic enzymes by angiotensin in cultured adrenal medullary cells. Molecular mechanisms and nature of second messenger systems. 196 64

Primary cultures of bovine adrenal medullary cells (AM) in a chemically defined media were used to examine the role of neural and hormonal factors in the expression of proenkephalin A (pEK), phenylethanolamine N-methyltransferase (PNMT) and tyrosine hydroxylase (TH) genes. Acetylcholine or nicotine reduced cellular content of catecholamines by 30% and increased the relative abundance of pEK, TH, and PNMT mRNAs. The increases produced by acetylcholine were +129%, +147%, and +43% for pEK, TH, and PNMT mRNA, respectively. The kinetics of increases produced by nicotine were different for the 3 mRNAs, with pEK and TH showing enhanced levels over 48 h incubation, while PNMT showed increase during the initial 18 h (+90%) followed by decline to control levels at 48 h. 8-Br cAMP and forskolin elicited a similar pattern of changes as nicotine, suggesting that cyclic AMP may be involved in the mediation of the nicotinic effects. To examine the role of depletion of cellular catecholamines in the regulation of mRNA levels, cells were exposed to tetrabenazine or reserpine. Decreases in cellular catecholamine contents were accompanied by increases in TH and pEK mRNA levels, while the expression of PNMT gene exhibited a transient 4-fold increase and then profound inhibition (60-95%) over a 48-h period. The tetrabenazine effect on TH and pEK mRNA was reduced by alpha-amanitin, suggesting transcriptionally-mediated regulation. Inductions of pEK but not TH or PNMT mRNAs were inhibited by cycloheximide. Hormonal regulation of TH, PNMT, and pEK mRNAs was examined by incubation of cells with dexamethasone. Low concentrations of dexamethasone (0.1, 10 nM) were effective to increase PNMT (+35%, +90%) and pEK (+27%, 45%) mRNA levels. TH mRNA was not affected by similar concentrations of dexamethasone, however, there was a 45% increase at 1 microM. Dexamethasone-elicited increases in PNMT mRNA levels were observed at 48 h and persisted up to 7 days, suggesting that hormonal mechanisms may be distinct from those mediating effects of nicotine, cAMP or tetrabenazine. Taken together, these results indicate that (1) the level of TH, PNMT, and pEK mRNAs are regulated by direct neural (acetylcholine) and hormonal (glucocorticoid) inputs to adrenal medullary cells; (2) effects of acetylcholine could be mediated by cyclic AMP and alterations in catecholamine content; and (3) expression of individual genes is regulated differentially. Such differential regulation of TH, PNMT, and pEK mRNAs may contribute to the long-term selective control of hormonal output from adrenomedullary cells.
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PMID:Coordinate and differential regulation of phenylethanolamine N-methyltransferase, tyrosine hydroxylase and proenkephalin mRNAs by neural and hormonal mechanisms in cultured bovine adrenal medullary cells. 197 May 6

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.
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PMID:Isolation of a rat adrenal cDNA clone encoding phenylethanolamine N-methyltransferase and cold-induced alterations in adrenal PNMT mRNA and protein. 257 95

Catecholamine content and in vitro activities of tyrosine hydroxylase (TH) and noradrenaline N-methyltransferase (NMT) were measured in cultures of isolated adrenal medullary cells from newborn and young postnatal rats to study the effects of the differentiation factors glucocorticoids and nerve growth factor (NGF). During the 4-day culture period the cellular catecholamine (CA) content and TH activity remained stable, whereas NMT activity dropped to about half of the initial level. In cells from 2- and 10-day-old rats 10 microM dexamethasone specifically prevented this loss in NMT activity. Furthermore, this glucocorticoid treatment increased, in a dose-dependent manner, the total CA content by 50-100% over control levels without changes in the adrenaline (A) proportion or TH activity. In contrast, NGF did not affect NMT activities at all. In cells from 10-day-old rats 100 ng/ml NFG elevated TH activity and total CA content to about 160% of controls and did not change the proportion of A. This increase in total CA content was linear with the NGF dose and required greater than 5 ng/ml NGF. In chromaffin cells from 2-day-old rats 100 ng/ml NGF affected neither TH activity nor the total content, whereas it significantly reduced the proportion of A by about 25%.
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PMID:Nerve growth factor and dexamethasone modulate synthesis and storage of catecholamines in cultured rat adrenal medullary cells: dependence on postnatal age. 286 27

We report here the isolation of a cDNA clone containing the full coding region of bovine phenylethanolamine N-methyltransferase (PNMTase, EC 2.1.1.28, S-adenosyl-L-methionine:phenylethanolamine N-methyltransferase). The complete nucleotide sequence of the cDNA has been determined, and the amino acid sequence of PNMTase deduced. Cultured cells transfected with an expression vector containing this cDNA produced high levels of PNMTase enzymatic activity. Antibodies specific for tyrosine hydroxylase [EC 1.14.16.2, tyrosine 3-monooxygenase; L-tyrosine, tetrahydrobiopterine: oxygen oxidoreductase (3-hydroxylating)], the first enzyme in the catecholamine pathway, possess a striking affinity for the PNMTase protein synthesized in vitro. Comparison of the deduced amino acid sequence of bovine PNMTase to rat tyrosine hydroxylase reveals that PNMTase shares significant homology with tyrosine hydroxylase and supports previous protein and immunological data suggesting that the catecholamine biosynthetic enzymes are structurally related.
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PMID:Complete nucleotide and deduced amino acid sequence of bovine phenylethanolamine N-methyltransferase: partial amino acid homology with rat tyrosine hydroxylase. 287 53

The pituitary-adrenocortical axis plays a complex role in the regulation of the levels of enzymes of the catecholamine biosynthetic pathway. In this report we have explored molecular mechanisms of these regulations, by examining the effects of hypophysectomy (HPX) and dexamethasone (DEX) on tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) mRNA levels in the adrenal medulla (AM) and superior cervical ganglia (SCG). Three weeks after hypophysectomy weights (-48%), total RNA (-49%), and DNA (-22%) contents in AM were significantly reduced, when compared to sham-operated animals (SO). In SCG decreases in weight (-23%) and in the ratio of RNA/DNA (-25%) were also found. TH mRNA contents paralleled decreases in total RNA levels and no significant change in the relative abundance of TH mRNA was found. When HPX rats were injected for 5 days with DEX (1 mg/kg, i.p.), TH mRNA levels in the SCG (+51%) and in the AM (+74%) were significantly increased when compared to saline-treated HPX animals. DEX given to SO rats increased TH mRNA in SCG (+49%); a 27% increase in TH mRNA in the AM was also observed. The relative abundance of PNMT mRNA in the AM was reduced after hypophysectomy (-64%). This decrease was completely reversed by DEX. In contrast, DEX did not affect PNMT mRNA levels in the AM of SO rats. PNMT mRNA was not detected in SCG of saline- or DEX-treated rats. In conclusion, our findings suggest that the pituitary-adrenocortical axis is involved in the regulation of the steady-state levels of TH and PNMT mRNAs. This regulation involves: (1) induction of TH mRNA contents in AM and SCG by increased plasma glucocorticoid levels; and (2) maintenance of the steady-state levels of PNMT mRNA in AM by glucocorticoid-dependent mechanisms.
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PMID:Regulation of tyrosine hydroxylase and phenylethanolamine N-methyltransferase mRNA levels in the sympathoadrenal system by the pituitary-adrenocortical axis. 290 43


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