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)

Environmental estrogenic pollutants are compounds that have been shown to have estrogenic effects on fetal development and reproductive systems. Less attention, however, has been paid to their influence on neuronal functions. We report here the effects of estrogenic pollutants on catecholamine synthesis in bovine adrenal medullary cells used as a model system of noradrenergic neurons. Treatment of cultured bovine adrenal medullary cells with p-nonylphenol and bisphenol A at 10 nM for 3 d stimulated [14C]catecholamine synthesis from [14C]tyrosine and tyrosine hydroxylase activity, an effect that was not inhibited by ICI 182,780, an antagonist of estrogen receptors. Significant effects of p-nonylphenol on [14C]catecholamine synthesis were observed at 0.1 nM, which is 45 times lower than that of the international regulatory standard (4.5 nM), and the maximum effects were around 10-100 nM. The concentrations (0.1-10 nM) used in the present study are similar to the range observed in rivers in the United States or Europe. On the other hand, short-term treatment of cells with 10 nM p-nonylphenol for 10 min also activated tyrosine hydroxylase, which was suppressed by U0126, an inhibitor of MAPK kinase. Furthermore, treatment of cells with p-nonylphenol for 5 min increased the phospho-p44/42MAPK in a concentration-dependent (1-1000 nM) manner, whereas p-nonylphenol (100 nm, 2 d) enhanced both levels of non-phospho- and phospho-p44/42MAPK. These findings suggest that short-term and long-term treatment of cells with estrogenic pollutants at environmental concentrations stimulates catecholamine synthesis and MAPK through an estrogen receptor-independent pathway.
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PMID:Stimulation of catecholamine synthesis by environmental estrogenic pollutants. 1548 22

To investigate the effect of estrogen on neuronal differentiation, especially on dopaminergic (DA) neurons, human neural stem cells (NSCs) were differentiated in the presence of 17beta-estradiol. NSCs gave rise to tyrosine hydroxylase (TH)-positive neurons in vitro, the proportion of which was increased by 17beta-estradiol. Increase in TH-positive neurons was abrogated by an estrogen receptor (ER) antagonist, ICI182780, suggesting ERs play a role in differentiation of DA neurons. The observation that ERs were expressed in both proliferating NSCs and postmitotic DA neurons suggested that increase in TH-positive neurons was due to induction and support of DA neurons. 17beta-Estradiol also increased the number of DA neurons derived from human NSCs in vivo when the cells were grafted into mouse brains. These results support a possible role for estrogen in the transplantation of NSCs for Parkinson's disease.
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PMID:Estrogen promotes differentiation and survival of dopaminergic neurons derived from human neural stem cells. 1561 91

For many populations of estrogen-sensitive neurons it remains unknown how they are associated with central nervous system circuitries that mediate estrogen-induced modulation of behavioral components. With the use of double-labeling immunohistochemistry and tracing techniques, the relationships of estrogen receptor (ER)-alpha- and ER-beta-immunoreactive (IR) neurons in the mouse brainstem and spinal cord to monoaminergic, cholinergic, and spinal projection systems are explored. Similar distributions of ER-IR neurons were present in females and males, with differences in labeling intensity of ER-alpha immunoreactivity among males and estrogen-, and oil-treated females. Barrington's nucleus, the ventrolateral medulla, and the nucleus of the solitary tract contained spinal-projecting ER-alpha-IR neurons, whereas ER-alpha-IR neurons in the periaqueductal gray, parabrachial nucleus, and catecholaminergic A1 cell group received spinal input. Numerous tyrosine hydroxylase (TH)-IR ER-alpha-IR neurons were present in the ventral periaqueductal gray, nucleus of the solitary tract, A1 cell group, and lumbosacral cord. The dorsal raphe nucleus contained ER-alpha-IR and ER-beta-IR neurons that colocalized with serotonin (5HT), and the reticulotegmental nucleus contained 5HT-IR ER-alpha-IR neurons. Fibers IR for vesicular acetylcholine transporter (VAChT), TH, and 5HT were located among ER-alpha-IR neurons in the dorsal horn and spinal autonomic regions. Robust staining for TH and VAChT, but not 5HT, was present among ER-alpha-IR neurons in the lumbosacral lateral collateral pathway. Possible modulatory actions of estrogen on each of these ER-IR populations are discussed in the context of their specific function, including micturition, sexual behavior, ejaculation, cardiovascular and respiratory control, tactile and nociceptive sensory processing, anti-nociception, endocrine regulation, and feeding.
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PMID:Estrogen receptor-alpha and -beta immunoreactive neurons in the brainstem and spinal cord of male and female mice: relationships to monoaminergic, cholinergic, and spinal projection systems. 1592 41

Regulation of gene expression is necessary to avoid possible adverse effects of gene therapy due to excess synthesis of transgene products. To reduce transgene expression, we developed a viral vector-mediated somatic regulation system using inducible Cre recombinase. A recombinant adeno-associated virus (AAV) vector expressing Cre recombinase fused to a mutated ligand-binding domain of the estrogen receptor alpha (CreER(T2)) was delivered along with AAV vectors expressing dopamine-synthesizing enzymes to rats of a Parkinson disease model. Treatment with 4-hydroxytamoxifen, a synthetic estrogen receptor modulator, activated Cre recombinase within the transduced neurons and induced selective excision of the tyrosine hydroxylase (TH) coding sequence flanked by loxP sites, leading to a reduction in transgene-mediated dopamine synthesis. Using this strategy, aromatic L-amino acid decarboxylase (AADC) activity was retained so that l-3,4-dihydroxyphenylalanine (L-dopa), a substrate for AADC, could be converted to dopamine in the striatum and the therapeutic effects of L-dopa preserved, even after reduction of TH expression in the case of dopamine overproduction. Our data demonstrate that viral vector-mediated inducible Cre recombinase can serve as an in vivo molecular switch, allowing spatial and temporal control of transgene expression, thereby potentially increasing the safety of gene therapy.
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PMID:Viral-mediated temporally controlled dopamine production in a rat model of Parkinson disease. 1618 9

Incubation of cultured bovine adrenal medullary cells with 17beta-estradiol (E(2)) (0.3-100nM) or membrane-impermeable E(2)-bovine serum albumin (100nM) acutely increased (14)C-catecholamine synthesis from [(14)C]tyrosine. The stimulatory effect of E(2) was not inhibited by ICI182,780, a nuclear estrogen receptor inhibitor. E(2) also increased tyrosine hydroxylase activity and p44/42MAPK phosphorylation, the former of which was attenuated by U0126, an inhibitor of p44/42MAPK kinase. The plasma membrane isolated from the gland showed two classes of specific binding sites of [(3)H]E(2) with apparent K(d)s of 3.2 and 106nM, and B(max)s of 0.44 and 8.5pmol/mg protein, respectively. The high-affinity binding of [(3)H]E(2) was most strongly inhibited by E(2) and phytoestrogens, and to lesser extents by other steroid hormones, while it was enhanced by ICI182,780 and environmental estrogenic pollutants. These findings suggest that E(2) acutely stimulates catecholamine synthesis via activation of p44/42MAPK through unique estrogen receptors in the plasma membrane of bovine adrenal medulla.
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PMID:Stimulation of catecholamine synthesis through unique estrogen receptors in the bovine adrenomedullary plasma membrane by 17beta-estradiol. 1630 25

Blood pressure in women increases after menopause, and sympathetic tone in female rats decreases with estrogen injections in the rostral ventrolateral medulla (RVLM) region that contains bulbospinal C1 adrenergic neurons and is involved in blood pressure control. We investigated the anatomical and physiological basis for estrogen effects in the RVLM. Neurons with alpha- or beta-subtypes of estrogen receptor (ER) immunoreactivity (-ir) overlapped in distribution with tyrosine hydroxylase (TH)-containing C1 neurons. Immunoelectron microscopy revealed that ERalpha- and ERbeta-ir had distinct cellular and subcellular distributions. ERalpha-ir was most commonly in TH-lacking profiles, many of which were axons and peptide-containing afferents that contacted TH-containing dendrites. ERalpha-ir was also in some TH-containing dendrites. ERbeta-ir was most frequently in TH-containing somata and dendrites, particularly on endoplasmic reticula, mitochondria, and plasma membranes. In whole-cell patch clamp recordings from isolated bulbospinal RVLM neurons, 17beta-estradiol dose-dependently reduced voltage-gated Ca(++) currents, especially the long-lasting (L-type) component. This inhibition was reversed by washing or prevented by adding the non-subtype-selective ER antagonist ICI182780. An ERbeta-selective agonist, but not an ERalpha-selective agonist, reproduced the Ca(++) current inhibition. The data indicate that estrogens can modulate the function of RVLM C1 bulbospinal neurons either directly, through extranuclear ERbeta, or indirectly through extranuclear ERalpha in selected afferents. Moreover, Ca(++) current inhibition may underlie the decrease in sympathetic tone evoked by local 17beta-estradiol application. These findings provide a structural and functional basis for the effects of estrogens on blood pressure control and suggest a mechanism for the modulation of cardiovascular function by estrogen in women.
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PMID:Evidence that estrogen directly and indirectly modulates C1 adrenergic bulbospinal neurons in the rostral ventrolateral medulla. 1669 57

The neuroactive steroids dehydroepiandrosterone (DHEA), its sulfate ester DHEAS, and allopregnanolone (Allo) are produced in the adrenals and the brain. Their production rate and levels in serum, brain, and adrenals decrease gradually with advancing age. The decline of their levels was associated with age-related neuronal dysfunction and degeneration, most probably because these steroids protect central nervous system (CNS) neurons against noxious agents. Indeed, DHEA(S) protects rat hippocampal neurons against NMDA-induced excitotoxicity, whereas Allo ameliorates NMDA-induced excitotoxicity in human neurons. These steroids exert also a protective role on the sympathetic nervous system. Indeed, DHEA, DHEAS, and Allo protect chromaffin cells and the sympathoadrenal PC12 cells (an established model for the study of neuronal cell apoptosis and survival) against serum deprivation-induced apoptosis. Their effects are time- and dose-dependent with EC(50) 1.8, 1.1, and 1.5 nM, respectively. The prosurvival effect of DHEA(S) appears to be NMDA-, GABA(A)- sigma1-, or estrogen receptor-independent, and is mediated by G-protein-coupled-specific membrane binding sites. It involves the antiapoptotic Bcl-2 proteins, and the activation of prosurvival transcription factors CREB and NF-kappaB, upstream effectors of the antiapoptotic Bcl-2 protein expression, as well as prosurvival kinase PKCalpha/beta, a posttranslational activator of Bcl-2. Furthermore, they directly stimulate biosynthesis and release of neuroprotective catecholamines, exerting a direct transcriptional effect on tyrosine hydroxylase, and regulating actin depolymerization and submembrane actin filament disassembly, a fast-response cellular system regulating trafficking of catecholamine vesicles. These findings suggest that neurosteroids may act as endogenous neuroprotective factors. The decline of neurosteroid levels during aging may leave the brain unprotected against neurotoxic challenges.
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PMID:Neurosteroids as endogenous inhibitors of neuronal cell apoptosis in aging. 1719 62

Although several studies have focused on the neuroprotective effects of estrogen (E2) on stroke, there have been tantalizing reports on the potential neuroprotective role of E2 in degenerative neuronal diseases such as Alzheimer's and Parkinson's (PD). In animal models of PD, E2 protects the nigrostriatal dopaminergic (DA) system against neurotoxins. However, little is known about the cellular and molecular mechanism(s) involved by which E2 elicits its neuroprotective effects on the nigrostriatal DA system. A preferred mechanism for neuroprotection is the interaction of E2 with specific neuroprotective growth factors and receptors. One such neuroprotective factor/receptor system is insulin-like growth factor-1 (IGF-1). E2 neuroprotective effects in the substantia nigra (SN) DA system have been shown to be dependent on IGF-1. To determine whether E2 also interacts with the IGF-1 receptor (IGF-1R) and to determine the cellular localization of estrogen receptor (ER) and IGF-1R, we compared the distribution of ER and IGF-1R in the SN. Stereological measurements revealed that 40% of the subpopulation of tyrosine hydroxylase-immunoreactive (TH-ir) SN pars compacta (SNpc) DA neurons are immunoreactive for estrogen receptor-beta (ERbeta). No immunolabeling for ERalpha was observed. In situ hybridization and immunocytochemistry studies confirmed the expression of IGF-1R mRNA and revealed that almost all TH-ir SNpc DA neurons were immunoreactive for IGF-1R, respectively. Moreover, one-third of glial fibrillary acidic protein (GFAP-ir) cells in the SN were ERbeta-ir, and 67% of GFAP-ir cells expressed IGF-1R-ir. Therefore, the localization of ERbeta and IGF-1R on SNpc DA neurons and astrocytes suggests a modulatory role of E2 on IGF-1R, and this modulation may affect neuroprotection.
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PMID:Distribution and localization patterns of estrogen receptor-beta and insulin-like growth factor-1 receptors in neurons and glial cells of the female rat substantia nigra: localization of ERbeta and IGF-1R in substantia nigra. 1748 15

17beta-Estradiol (E2) has been shown to exert antiarrhythmic effect after myocardial infarction; however, the mechanisms remain unclear. This study was performed to determine whether E2 exerts beneficial effects through attenuated sympathetic hyperreinnervation after infarction. Two weeks after ovariectomy, female Wistar rats were assigned to coronary artery ligation or sham operation. Twenty-four hours after coronary ligation, rats underwent one of five treatments: 1) sc vehicle treatment (control), 2) sc E2 treatment, 3) sc E2 treatment + tamoxifen (a potent estrogen receptor antagonist), 4) bosentan (an endothelin receptor blocker), or 5) sc E2 treatment + bosentan and followed for 4 wk. Myocardial endothelin-1 and norepinephrine levels at the remote zone revealed a significant elevation in control infarcted rats, compared with sham-operated rats, which is consistent with sympathetic hyperinnervation after infarction. Sympathetic hyperinnervation was blunted after giving the rats either E2 or bosentan, assessed by immunohistochemical analysis of tyrosine hydroxylase, growth-associated protein 43 and neurofilament, and Western blotting and real-time quantitative RT-PCR of nerve growth factor. Arrhythmic scores during programmed stimulation in E2-treated infarcted rats were significantly lower than in control-infarcted rats. Addition of bosentan did not have additional beneficial effects, compared with rats treated with E2 alone. The beneficial effect of E2 on sympathetic hyperinnervation was abolished by tamoxifen. Our data indicated that E2 has a role for sympathetic hyperinnervation after infarction, probably through an endothelin-1-depedent pathway. Chronic administration of E2 after infarction may attenuate the arrhythmogenic response to programmed electrical stimulation.
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PMID:Physiological concentration of 17beta-estradiol on sympathetic reinnervation in ovariectomized infarcted rats. 1804 98

Receptive female hamsters display very rigid lordotic postures. Estradiol facilitates this behavior via activation of estrogen receptors. In the hamster brainstem estrogen receptor-alpha-immunoreactive neurons (ER-alpha-IR) are present in various brainstem regions including nucleus retroambiguus (NRA) in the caudal ventrolateral medulla (CVLM) and nucleus of the solitary tract. ER-alpha-IR neurons in the CVLM project to the thoracic and upper lumbar cord. However, A1 neurons in this region do not project to the spinal cord, in contrast to overlapping C1 neurons. The question now arises: are ER-alpha-IR cells in the CVLM part of the A1/C1 group, or do they belong to the NRA or do they compose a separate cluster. A study in ovariectomized female hamsters using a combination of double immunostaining and retrograde tracing techniques and measurement of soma diameters was carried out. The results showed that A1/C1 neurons in the CVLM are almost never ER-alpha-positive; neurons inside or bordering the NRA can be divided in two different types: large multipolar and small; the large NRA-neurons, projecting caudally, are neither tyrosine hydroxylase- (TH) nor ER-alpha-IR; the small neurons, bordering the NRA and projecting caudally, are ER-alpha-IR but not TH-IR. From the available evidence and the present findings it can be concluded that the group of small ER-alpha-IR neurons in the CVLM has to be considered as a distinct entity, probably involved in the autonomic physiological changes concurring with successive phases of the estrous cycle. Because the location is closely related to the NRA itself the nucleus is called nucleus para-retroambiguus, abbreviated (NPRA).
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PMID:The nucleus para-retroambiguus: a new group of estrogen receptive cells in the caudal ventrolateral medulla of the female golden hamster. 1807 82


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