Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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An alkaline phosphatase-labelled anti-sense oligonucleotide probe specific for tyrosine hydroxylase (TOH) mRNA has been used for visualisation of TOH mRNA in the rat brain and adrenal gland. Both ribonuclease pre-treatment and the use of excess non-labelled probe abolished the specific hybridization signal. Furthermore the TOH mRNA-positive signal was only found in cells known from earlier studies to react with anti-TOH antibodies. To determine if the alkaline phosphatase-labelled probe could be used in a semiquantitative manner for measurement of the density of TOH mRNA signal, we used reserpine pre-treatment which induces TOH mRNA expression. The results revealed a significant increase in TOH mRNA signal in locus coeruleus and substantia nigra neurons, and in adrenal medulla chromaffin cells. The increased signal in these areas agreed with the increase in TOH mRNA signal previously observed by Northern analysis and suggests that this type of alkaline phosphatase-labelled probe allows sensitive detection of changes in TOH gene expression.
Brain Res Mol Brain Res 1990 Apr
PMID:Sensitive non-radioisotopic in situ hybridization histochemistry: demonstration of tyrosine hydroxylase gene expression in rat brain and adrenal. 197 Aug 45

Peripheral afferent denervation (deafferentation) of the rodent main olfactory bulb produces a marked decrease in tyrosine hydroxylase (TH) activity and immunoreactivity in a population of juxtaglomerular dopaminergic neurons. Preservation of activity and immunostaining for aromatic L-amino acid decarboxylase implies that these cells do not die, but change phenotype. We now report that the steady-state level of TH mRNA markedly decreases in the adult mouse olfactory bulb in response to deafferentation. This reduction is permanent following intranasal irrigation with 0.17 M zinc sulphate (ZnSO4) but reversible following deafferentation produced by intranasal irrigation with 0.7% Triton X-100. The initial declines in TH activity, protein and mRNA of dopaminergic juxtaglomerular neurons observed after Triton X-100 treatment are all reversible as the steady-state level of TH mRNA gradually returns to control levels. Steady-state levels of mRNA for olfactory marker protein (OMP), a protein found in high concentrations in olfactory receptor neurons and their processes which innervate the olfactory bulb, were also monitored following deafferentation. Following treatment with either ZnSO4 or Triton X-100, the pattern of changes in steady-state levels of OMP mRNA was similar to that observed for TH. The steady-state level of PEP19 mRNA, a peptide previously localized to granule cells in the olfactory bulb, was not altered by deafferentation. These data indicate selective and parallel regulation of TH and OMP message and protein levels following deafferentation.
Brain Res Mol Brain Res 1990 Feb
PMID:Transneuronal regulation of neuronal specific gene expression in the mouse olfactory bulb. 197 Oct 84

Presynaptic autoreceptor-mediated modulation of dopamine (DA) synthesis was evaluated as the inhibition of tyrosine hydroxylase activity by enantiomeric mono- and dihydroxyaporphines with minced striatal tissue from rat brain. The isomers of N-n-propylnorapomorphine (NPA) both inhibited tyrosine hydroxylase activity [IC50 = 0.3 and 1.0 microM for (R)-(-)- and (S)-(+)-NPA, respectively; R/S potency = 3.6]. Their effects were fully blocked by the nonselective DA receptor antagonist fluphenazine, as well as by the D2-selective antagonist spiperone, but not by the D1 antagonist SCH-23390. These results suggest a D2-type autoreceptor-mediated inhibition of DA synthesis, with limited enantiomeric selectivity of this catechol-aporphine. The corresponding monohydroxy analogs, (R)-(-)- and (S)-(+)-11-hydroxy-N-n-propylnoraporphine (11-OH-NPa) were about 100 times less potent (IC50 = 42 and 87 microM, respectively) than the NPA isomers in fully inhibiting the enzyme activity in normal tissue but, after depletion of endogenous DA by acute in vivo pretreatment with reserpine (which did not alter the number of D1 or D2 specific binding sites), (R)-(-)-11-OH-NPa was a highly potent but partial agonist (IC25 = 7 nM). Fluphenazine and spiperone fully antagonized the inhibition of tyrosine hydroxylase by (R)-(-)-11-OH-NPa in reserpinized tissue, but SCH-23390 was ineffective. Actions mediated by endogenous DA probably contribute to the effect of high concentrations of (R)-(-)-11-Oh-NPa to evoke a full inhibition of DA synthesis, but its high potency partial agonist effects appear to be mediated by D2-autoreceptors. (S)-(+)-11-OH-NPa was a very weak partial agonist in reserpinized tissue, with an IC25 = 30 microM (essentially the same as normal tissue); thus, (R)-(-)-11-OH-NPa was greater than 4,000 times more potent than its S-(+)-enantiomer in the absence of endogenous DA. These results demonstrate that NPA, which contains a catechol moiety, acts as a full agonist to inhibit striatal DA synthesis via a presynaptic autoreceptor of the D2 type, with only slight stereoselectivity, and that its monohydroxy analog is a very potent but partial D2 autoreceptor agonist, with very high stereoselectivity.
Mol Pharmacol 1990 Jul
PMID:Presynaptic inhibition of dopamine synthesis in rat striatal tissue by enantiomeric mono- and dihydroxyaporphines. 197 25

The interaction between cell-cell contact and cyclic AMP-mediated control of the rat tyrosine hydroxylase (TH) gene was investigated in subclones of the PC12 rat pheochromocytoma cell line. Increasing cell culture density and elevation of intracellular cyclic AMP levels with forskolin both cause augmentation of TH RNA levels. However, the extent of increase in TH RNA following forskolin treatment is less in cultures grown at high density than those at low density, suggesting that there may be an interaction in the mechanism by which these two treatments modulate TH RNA levels. The role of cis-acting sequences in the TH gene in the induction of TH RNA by cyclic AMP and cell density was determined by the use of plasmid constructs containing the 5'-flanking sequences of the TH gene directing the transcription of the reporter gene, chloramphenicol acetyltransferase (CAT). Using transient transfection assays in PC12 cells, we have mapped the site of cyclic AMP regulation of the TH gene to a region between -60 and -41. Stable transformants of PC12 cells which express p5'TH CAT (-773/+27) were isolated and the activity of CAT following treatment of cells with forskolin and growth at different cell densities was evaluated. CAT activity does not differ between cells grown at low or high density. Forskolin induces CAT activity 2-4 fold, but the extent of induction does not vary with changes in cell culture density. We conclude from these experiments that the intracellular mechanism by which increased cell-cell contact modulates TH RNA levels is not through interaction with the same genomic elements as those which regulate gene expression by cyclic AMP.
Brain Res Mol Brain Res 1990 Jun
PMID:Interaction of cyclic AMP and cell-cell contact in the control of tyrosine hydroxylase RNA. 197 15

The effects of aging in the female rat were analyzed in terms of tyrosine hydroxylase (TH) gene expression and serum prolactin levels. The number of tuberoinfundibular dopaminergic (TIDA) neurons and the concentration of TH mRNA per cell was greater in 16- to 18-month-old rats than in 25-month-old rats. The amount of TH immunostaining was more intense in the median eminence of the 18-month-old rats compared to either younger or older rats. Plasma prolactin levels were moderately elevated in 18-month-old rats compared to 4-month-old rats, and extremely elevated in 25-month-old rats due to the occurrence of pituitary prolactinomas. There were no detectable changes in TH mRNA levels in the substantia nigra with age, whereas adrenal TH mRNA increased with age. We propose that prolactin initially exerts a stimulatory effect on the TIDA neurons as the rat ages, but eventually causes a loss in neuronal number and neuronal function as the pituitary prolactinoma secretes increased amounts of prolactin.
Brain Res Mol Brain Res 1990 Jun
PMID:Tyrosine hydroxylase messenger RNA in the hypothalamus, substantia nigra and adrenal medulla of old female rats. 197 16

Bronchial reactivity changes during childhood, indicating possible changes in neural control. Nerves supplying the intrapulmonary airways were therefore studied in autopsy tissue from 14 normal infants (0 to 3.5 yr), 3 children (8.3 to 10.75 yr), and 4 adults (17 to 24 yr). An indirect immunofluorescence technique was used to study the distribution and relative number of nerve fibers containing the general neuronal markers protein gene product 9.5 and synaptophysin. Nerve subpopulations were identified using antisera to neuropeptide tyrosine, vasoactive intestine polypeptide, somatostatin, substance P, calcitonin gene-related peptide, and the enzyme tyrosine hydroxylase. Between birth and 3 yr, the distribution and relative number of immunoreactive nerves shown by both the general neuronal markers and specific antisera did not change. Neuropeptide tyrosine-immunoreactive nerves were the most common peptide-containing nerve subpopulation identified in the human lung, supplying bronchial smooth muscle, submucosal glands, cartilage, and submucosa. Other peptide-containing nerves exhibited distinct distribution patterns. Two differences in the airway innervation were identified between cases aged 0 to 3.5 yr and the older age groups. Relatively fewer peptide-containing nerves occurred in the adult bronchioli and respiratory unit, but the relative number of vasoactive intestinal polypeptide-containing nerves supplying the bronchial and bronchiolar smooth muscle was greater in the two older age groups. Given these apparent age-related differences in the number of peptide-containing nerves supplying the human airway, studies on the development of peptide receptors are indicated.
Am J Respir Cell Mol Biol 1990 Sep
PMID:Immunohistochemical localization of peptide-containing nerves in human airways: age-related changes. 197 91

Membrane depolarization has been widely used to elucidate the response of the nervous system to prolonged neuronal activity or stress. We studied the effect of treating PC12 cells with membrane depolarizing stimuli, 50 mM KCl, or 150 microM veratridine, and the subsequent changes in the mRNA levels of the catecholamine biosynthetic enzymes, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH). TH mRNA levels were found to increase 2- to 5-fold after continuous treatment for 1-12 h with 50 mM KCl. Depolarization with 150 microM veratridine had a similar effect on TH mRNA. In contrast, DBH mRNA levels were unchanged by either KCl or veratridine treatment. The role of calcium in the increase of TH mRNA levels elicited by depolarization was examined. The increase in TH mRNA was inhibited by the chelation of calcium with 3 mM EGTA. However, in contrast to their effect on phosphorylation of TH elicited by acute depolarization, the calcium channel blockers, nitrendipine and verapamil, and the calmodulin antagonists, W7 and trifluoperazine, did not prevent the increase in TH mRNA levels subsequent to several hours exposure to depolarizing stimuli. The calcium ionophore, A23187, alone was unable to induce TH mRNA levels. Thus, the increase in TH mRNA elicited by depolarization is mediated differently than the acute phosphorylation of the enzyme.
Brain Res Mol Brain Res 1990 Jul
PMID:Differential effect of membrane depolarization on levels of tyrosine hydroxylase and dopamine beta-hydroxylase mRNAs in PC12 pheochromocytoma cells. 197 98

We have previously shown that the mRNA for human tyrosine hydroxylase (TH) exists in one of 4 forms as a result of alternative splicing of intron 1. In order to determine the tissue-specific expression of the multiple human transcripts we have utilized specifically primed polymerase chain reactions (PCR) in combination with reverse-transcribed RNA. Using PCR analysis we determined that many human neuronal tissues express all 4 forms of human TH (hTH-1-4); however, hTH-3 and -4 are generally expressed at less than 1% of the other two. Of all tissues examined, only pancreatic beta-islet cells expressed a single form of human TH mRNA (hTH-2). The mRNA for rat TH is present in only one form, the equivalent of hTH-1. Since we have shown that the human genes for TH and insulin are only 2.7 kb apart and several groups have reported insulin-like expression in neuronal tissues, we looked for insulin transcription in the same central and peripheral nervous system samples. Insulin mRNA was not present within the limits of detection.
Brain Res Mol Brain Res 1990 Jul
PMID:Analysis of tyrosine hydroxylase and insulin transcripts in human neuroendocrine tissues. 197 99

We reported previously that, following phosphorylation by cyclic AMP-dependent protein kinase, tyrosine hydroxylase in rat corpus striatal extracts is inactivated in a time-dependent and apparently irreversible fashion. Removal of low molecular weight substances from these extracts by gel filtration attenuates this inactivation. We tried to determine the identity of endogenous metabolites that promote inactivation of tyrosine hydroxylase under our experimental conditions. In the present study, we report that the reducing co-substrate tetrahydrobiopterin and its analogues promoted this irreversible inactivation. The concentration that produced a 50% loss of activity (at 20 min) of the phosphorylated enzyme was 0.7 microM and that for the unphosphorylated enzyme was 420 microM. Using enzyme purified from a rat pheochromocytoma, we found that tyrosine, alpha-methyl-p-tyrosine, and a 3-iodotyrosine protected the phosphorylated enzyme against the inactivation produced by tetrahydrobiopterin. Catecholamines (dopamine, norepinephrine, epinephrine, and some of their analogues) also nullified inactivation. In contrast, the product of the reaction, dihydroxyphenylalanine, failed to attenuate the inactivation process. We performed several studies to ascertain the mechanism of inhibition by tetrahydrobiopterin. We considered the possibility that it formed reactive free radicals that produced inhibition. Free radical scavengers, however, failed to block the inhibition produced by tetrahydrobiopterin. Superoxide dismutase, catalase, and peroxidase also failed to protect tyrosine hydroxylase against inactivation. Moreover, when the experiments were performed under anaerobic conditions, the inactivation process was unaffected. These results suggest that reactive oxygenated species were not required for inactivation by tetrahydrobiopterin.
Mol Pharmacol 1990 Oct
PMID:Inactivation of tyrosine hydroxylase by pterin substrates following phosphorylation by cyclic AMP-dependent protein kinase. 197 41

Unilateral naris cauterization in rats results in occlusion of the affected naris and blockade of odorant access to ipsilateral olfactory receptor cells in the olfactory epithelium. These receptor cells project exclusively to the olfactory bulb (OB) and appear to regulate expression of the dopaminergic phenotype in a population of OB juxtaglomerular neurons. Unilateral odor deprivation results in a loss of normal stimulatory input to the OB and a marked and specific decrease in ipsilateral OB tyrosine hydroxylase (TH) expression. The expression of co-localized aromatic L-amino acid decarboxylase (AADC) is not similarly affected. We have used this procedure in neonatal rats to examine the effect of stimulus deprivation on OB TH and AADC mRNA levels. Both Northern blot and in situ hybridization analyses revealed a pronounced decrease in ipsilateral as compared to contralateral OB TH mRNA levels 40 days after naris closure. In contrast, the levels of OB AADC mRNA were unaltered by naris closure. By in situ hybridization histochemistry, both TH and AADC mRNAs were localized to OB juxtaglomerular neurons. Odor deprivation was associated with an apparent region-specific reduction in TH mRNA within the ipsilateral OB glomerular layer. By densitometric analysis, the loss of TH-specific message was quantitatively consistent with the decrease in TH activity, suggesting that the observed plasticity of OB dopaminergic neurons following functional deafferentation can be attributed to a selective, transneuronally-mediated down regulation of TH gene transcription.
Brain Res Mol Brain Res 1990 Oct
PMID:Decrease in tyrosine hydroxylase, but not aromatic L-amino acid decarboxylase, messenger RNA in rat olfactory bulb following neonatal, unilateral odor deprivation. 198 Jan 39


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