Disease relevance of Th

• Tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, is induced by hypoxia in oxygen-sensitive cells of the carotid body and pheochromocytoma-derived PC12 cells [1].
• These results indicate that HIFs may play an important role in regulation of TH gene expression in oxygen-sensitive cells and also in the development of hypercatecholaminemia in pheochromocytoma tumors [1].
• Tyrosine hydroxylase, but not dopamine beta-hydroxylase, is increased in rat frontal cortex after traumatic brain injury [2].
• Maximal elevation in TH mRNA levels occurred after single immobilization for two hours and subsequent decapitation 24 hours later [3].
• Genomic DNA encoding the rat tyrosine hydroxylase (TH) gene was isolated from a lambda phage library using a nick-translated fragment from a cDNA clone for rat TH [4].

Psychiatry related information on Th

• In addition to TH, changes in DBH and GTPCH gene expression may also contribute to the development of stress-triggered affective disorders [5].
• Effects of various inhibitors of tyrosine hydroxylase and dopamine beta-hydroxylase on rat self-stimulation after reserpine treatment [6].
• Furthermore, administration of either the benzodiazepine receptor agonist diazepam or the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine prevented the increase in urinary isatin excretion induced by acute food deprivation, whereas the dopamine-beta-hydroxylase inhibitor diethyldithiocarbamate proved ineffective [7].
• Repeated electroconvulsive shock (ECS) treatment (once per day for 7 days) produced a significant increase in tyrosine hydroxylase activity, GTP-cyclohydrolase activity and tetrahydrobiopterin (BH4) levels in the locus ceruleus and hippocampus from 1 to 4 days after the last treatment [8].
• The effects of the inhibitor of the tyrosine-hydroxylase H 44/68 and the inhibitor of the dopamine-beta-hydroxylase FLA 63 on the diurnal variations of the motor activity was studied in male Wistar rats, which were kept under standardized conditions of light and darkness (L:D = 12:12 h) [9].

High impact information on Th

• EGF but not insulin enhances the phosphorylation of tyrosine hydroxylase [10].
• NGF, CT and cAMP enhance phosphorylation of the same set of proteins including tyrosine hydroxylase, ribosomal protein S6, histones H1 and H3, and the nonhistone chromosomal and cytoplasmic high mobility group (HMG) 17 protein, and reduce phosphorylation of H2A [10].
• This was associated with enhanced tyrosine hydroxylase (TH) immunoreactivity in the striatum in the area around the transplanted Sertoli cells [11].
• We report here that axotomy resulted in loss of half the tyrosine hydroxylase-expressing neurons in the substantia nigra [12].
• We have found, in the rat superior cervical ganglion, that a postsynaptic biochemical consequence of preganglionic nerve stimulation, namely the acute activation of tyrosine 3-monooxygenase (tyrosine hydroxylase, TH; EC 1.14.16.2), is mediated in part by acetylcholine and in part by a non-cholinergic neurotransmitter [13].

Chemical compound and disease context of Th

• Tyrosine hydroxylase (TH) gene transcription rate is stimulated by cyclic AMP in cultured rat pheochromocytoma cells [14].
• Our data support the hypothesis of an AT(1)/AT(2) receptor cross-talk in the adrenomedullary ganglion cells, and a role for both receptor types on the selective regulation of basal NE, but not epinephrine formation, and in the regulation of basal TH transcription [15].
• If one assumes that the up-regulations in TH and alpha(2B)-adrenoceptor gene expression are indicative of increased sympathetic nervous activity, then, these altered gene expressions could be responsible for the maintenance of high blood pressure in male and testosterone-treated female cafeteria-fed rats [16].
• We report here that maternal hypoxia (11-13% O2) leads to 2-3-fold increases (p < 0.01) in fetal adrenal TH, DBH, and NPY mRNA levels on the day before birth [17].
• Levodopa-responsive infantile parkinsonism due to a novel mutation in the tyrosine hydroxylase gene and exacerbation by viral infections [18].

Biological context of Th

• Preloading of neurons with p62-pep (a peptide containing consenses of mitogen-activated protein kinase in p62) resulted in a loss of Ang II-induced p62 phosphorylation and stimulation of NET and TH messenger RNA levels [19].
• Mapping the TH promoter showed that the putative half estrogen response element (ERE) motif at - 675, as well as the activation protein 1 motif at - 205, were not required for response to E2 with either ER [20].
• Thus, three different signal transduction systems appear to mediate the physiological regulation of tyrosine hydroxylase phosphorylation at three different sites [21].
• Finally, the enhanced TH promoter activity was competitively attenuated by expression of a plasmid containing the ATF-2 transactivation domain [22].
• First, by using reporter constructs, we found that the transcription mediated by cAMP-responsive element (CRE) was selectively enhanced in the V-1 cells, and TH promoter activity was totally dependent on the CRE in the promoter region of the TH gene [22].

Anatomical context of Th

• Furthermore, depletion of MARCKS by MARCKS-AON treatment of neurons resulted in a significant decrease in Ang II-stimulated accumulation of TH and DbetaH immunoreactivities and [3H]NE uptake activity in synaptosomes [23].
• A similar decline in the ratio of TH mRNA-containing to TH-immunoreactive cells was not observed in sympathetic ganglia [24].
• PC12 cells, transiently co-transfected with expression vector for ERalpha or ERbeta, and luciferase gene under control of the TH promoter, were treated with 17 beta-estradiol (E2) [20].
• In contrast, TH and DBH mRNA levels in the SCG, but not in adrenal medulla, were elevated by ACTH administration, similar to the levels attained after immobilization [25].
• Repeated stress elevated expression of all the genes studied and increased TH immunoreactivity in both ganglia [25].

Associations of Th with chemical compounds

• Moreover, E2 attenuated the increase in TH transcription seen with cyclic AMP analogs [20].
• Thus, TH is transcriptionally regulated by estradiol in opposite directions depending on ER subtype [20].
• The results show that there was no difference in TH mRNA content; however, DBH mRNA levels in areas A1, A2, and C1 of the middle-aged animals did not rise during the surge as was observed in the young animals [26].
• Prolonged cortisol administration failed to alter the mRNA levels of TH, DBH, and NPY in control animals but attenuated the response to stress [25].
• The increase in TH may reflect a compensatory response of dopaminergic neurons to upregulate their synthesizing capacity and increase the efficiency of dopamine neurotransmission chronically after TBI [2].

Physical interactions of Th

• In the SN, treatment with TIQ alone did not change TH level although it enhanced DA content and decreased [(3)H]GBR 12,935 binding to DAT in the substantia nigra pars compacta (SNc) [27].
• AP-1 complex and c-fos transcription are involved in TPA provoked and trans-synaptic inductions of the tyrosine hydroxylase gene: insights into long-term regulatory mechanisms [28].
• Hypoxia-induced protein binding to O2-responsive sequences on the tyrosine hydroxylase gene [29].
• The higher tyrosine hydroxylase activity was paralleled with significantly higher D2 binding values in the corpus striatum and olfactory tubercle of Fischer 344 rats [30].
• The fact that the increase of mRNA parallels the appearance of labelled neurotensin in the substantia nigra indicates that the changes in the gene expression of tyrosine hydroxylase might be the consequence of the retrograde axonal transport of neurotensin [31].

Enzymatic interactions of Th

• Tryptic digestion of tyrosine hydroxylase phosphorylated by calcium/calmodulin-dependent protein kinase yields three distinct 32P-peptide peaks, which are identical to those phosphorylated by treatment of intact PC12 cells with either high K+ or A23187 [32].
• Immunostaining using tyrosine hydroxylase (TH) and cleaved caspase-3 antibodies demonstrated that caspase-1 and -3 inhibitors reduce caspase-3 activation as well as overall cell death [33].

Co-localisations of Th

• Tyrosine hydroxylase immunoreactivity colocalized in 18% of ERbeta immunoreactive cells in d 21 females [34].
• In ciliary neurons of both control and sympathectomized rats, neuropeptide Y immunoreactivity was preferentially co-localized with tyrosine hydroxylase [35].
• Neither tyrosine hydroxylase nor neuropeptide Y-immunoreactivity was co-localized in CGRP-containing fibers [36].
• Immunoreactivities for gamma-aminobutyric acid (GABA) and the dopamine-synthesizing enzyme tyrosine hydroxylase (TH) were localized ultrastructurally and colocalized at the light microscopic level in neurons of the rat main olfactory bulb [37].
• Double labelling studies revealed that synaptotagmin I co-localized with tyrosine hydroxylase, a marker of sympathetic adrenergic neurons, and with substance P, a marker for sensory neurons [38].

Regulatory relationships of Th

• Galanin inhibits tyrosine hydroxylase expression in midbrain dopaminergic neurons [39].
• In collaboration with cAMP, Phox2a can induce expression of TH but not of DBH or of panneuronal genes [40].
• Urocortin 2 induces tyrosine hydroxylase phosphorylation in PC12 cells [41].
• Glial cell line-derived neurotrophic factor modulates ischemia-induced tyrosine hydroxylase expression in rat hippocampus [42].
• Semichronic inhibition of glutathione reductase promotes oxidative damage to proteins and induces both transcription and translation of tyrosine hydroxylase in the nigrostriatal system [43].

Other interactions of Th

• These studies demonstrate that NGF can signal retrogradely to mediate the induction of TH and p75NTR mRNAs [44].
• Angiotensin II (Ang II) interaction with the neuronal AT1 receptor results in a chronic stimulation of neuromodulation that involves the expression of norepinephrine transporter (NET) and tyrosine hydroxylase (TH) [19].
• We also show that some of the effects of pVHL on activity of the TH promoter are mediated through HIFs [1].
• Isolation stress increases tyrosine hydroxylase mRNA in the locus coeruleus and midbrain and decreases proenkephalin mRNA in the striatum and nucleus accumbens [45].
• Ovaries in both PCO and PCO anti-NGF groups decreased in size as well as in number and size of corpora lutea. mRNA expression of alpha1a-AR and TrkA in the ovaries was lower, whereas expression of alpha1b- and alpha1d-AR and TH was higher, in the PCO group than in controls [46].

Analytical, diagnostic and therapeutic context of Th

• After Day E12 TH mRNA cannot be detected in enteric or vagal cells by in situ hybridization; nevertheless, TH immunoreactivity continues to be present through Day E14 [24].
• Our results show a severalfold increase in the relative abundance of TH and NPY mRNAs in response to a single immobilization [25].
• No alterations in DBH levels were observed by Western blot at any time point examined, but there was a significant increase in TH expression 28 days after TBI (optical density 334 +/- 68% or 3.3-fold, ipsilateral and 218 +/- 39% or 2.2-fold, contralateral) relative to the sham controls [2].
• The intensity of both the TH and DBH immunofluorescence decreased as the glands and their innervation developed [47].
• Semi-quantitative RT-PCR and quantitative immunoblotting experiments revealed that GAL had no effect on TH mRNA levels in VM cultures but reduced TH protein [39].

References