EC:1.14.16.2 - FACTA Search

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)

The classical view of norepinephrine transporter (NET) function is the re-uptake of released norepinephrine (NE) by mature sympathetic neurons and noradrenergic neurons of the locus ceruleus (LC; [1-3]). In this report we review previous data and present new results that show that NET is expressed in the young embryo in a wide range of neuronal and non-neuronal tissues and that NET has additional functions during embryonic development. Sympathetic neurons are derived from neural crest stem cells. Fibroblast growth factor-2 (FGF-2), neurotrophin-3 (NT-3) and transforming growth factor-beta1 (TGF-beta1) regulate NET expression in cultured quail neural crest cells by causing an increase in NET mRNA levels. They also promote NET function in both neural crest cells and presumptive noradrenergic cells of the LC. The growth factors are synthesized by the neural crest cells and therefore are likely to have autocrine function. In a subsequent stage of development, NE transport regulates differentiation of noradrenergic neurons in the peripheral nervous system and the LC by promoting expression of tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH). Conversely, uptake inhibitors, such as the tricyclic antidepressant, desipramine, and the drug of abuse, cocaine, inhibit noradrenergic differentiation in both tissues. Taken together, our data indicate that NET is expressed early in embryonic development, NE transport is involved in regulating expression of the noradrenergic phenotype in the peripheral and central nervous systems, and norepinephrine uptake inhibitors can disturb noradrenergic cell differentiation in the sympathetic ganglion (SG) and LC.
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PMID:Norepinephrine transporter expression and function in noradrenergic cell differentiation. 1110 37

Functional expression of norepinephrine transporter (NET) and its regulation were examined in rat pheochromocytoma cell line, PC12. Nerve growth factor (NGF) decreased [3H]-norepinephrine (NE) uptake in association with a decrease in NET mRNA levels. On the other hand, levels of tyrosine hydroxylase mRNA increased in PC12 cells treated with NGF for 4-24 h, while Oct-2 mRNA levels decreased at 4 h with NGF then recovered for 8-24 h in the presence of NGF. Both bFGF and EGF reduced [3H]NE uptake, although they failed to affect NET mRNA levels. To examine the NET transcriptional regulation, we identified the 5'-noncoding region of rat NET mRNA by the rapid amplification of cDNA end (RACE) method and cloned the 5'-flanking region of NET gene. The newly identified exon encodes the untranslated region of rat NET mRNA upstream of the known 5'-region including ATG start codon. Constructs having green fluorescent protein (GFP) as reporter were made with the cloned NET gene, and promoter activity was examined in CHO and SK-N-SH cells transiently transfected and in PC12 cells stably transfected with NET-GFP constructs. The results indicate that the 2.1 kb NET flanking region displays promoter activity and is responsible for the NGF-induced down-regulation of NET expression.
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PMID:Nerve growth factor down-regulates the expression of norepinephrine transporter in rat pheochromocytoma (PC12) cells. 1116 76

Responses of central noradrenergic (NE) neurons to stressors like immobilization (IMO), cold exposure, insulin-induced hypoglycemia, and cellular glucoprivation caused by 2-deoxy-D-glucose (2-DG) were investigated in intact and long-term repeatedly immobilized (LTR, 2 h daily IMO for 41 days) rats. Expression of tyrosine hydroxylase (TH), norepinephrine transporter (NET) and vesicular monoamine transporter (VMAT2) genes were determined by using in situ hybridization histochemistry in brainstem A1, A2, A5 and locus coeruleus (LC) neurons. TH mRNA levels were increased by single IMO or 2-DG administration in all areas studied. Cold was effective only in LC and A2 neurons while insulin had no effect. LTR immobilization elevated TH mRNA levels in all investigated cell groups. These elevations were equally high to those elicited by a single IMO in each noradrenergic group, except the LC where LTR IMO was less effective than the single IMO. The levels of NET and VMAT2 mRNAs were elevated only in the A1 and A2 cell groups of LTR IMO rats. A newly applied IMO in LTR rats did not alter TH, NET, and VMAT2 mRNA levels in any NE cell group investigated. Novel stressors like cold and 2-DG exaggerated the increased TH mRNA levels only in the LC of LTR IMO rats, unlike in the other NE cell groups. The present data indicate that repeated exposure of rats to homotypic stressor induces an adaptation of NE neurons, whereas single exposure of such animals to heterotypic novel stressor produces an exaggerated response of the system at the level of TH (in LC) and NET (in A1, A2) gene expression.
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PMID:Effect of novel stressors on gene expression of tyrosine hydroxylase and monoamine transporters in brainstem noradrenergic neurons of long-term repeatedly immobilized rats. 1131 64

We report the isolation, functional characterization, and localization of a Na(+)/Cl(-)-dependent catecholamine transporter (meNET) present in the brain of the teleost fish medaka. This carrier is very similar to the human neuronal norepinephrine transporter (NET) and the human neuronal dopamine transporter (DAT), showing 70 and 64% amino acid identity, respectively. When expressed in COS-7 cells, this transporter mediates the high-affinity uptake of dopamine (K(M) = 290 nM) and norepinephrine (K(M) = 640 nM). Its pharmacological profile reveals more similarities with NET, including a high affinity for the tricyclic antidepressants desipramine (IC(50) = 0.92 nM) and nortriptyline (IC(50) = 16 nM). In situ hybridization on the medaka brain shows that meNET mRNA is present only in a subset of tyrosine hydroxylase-positive neurons found in the noradrenergic areas of the hindbrain, such as the locus ceruleus and area postrema. None of the dopaminergic areas anterior to the isthmus contains any labeled neurons. Neither reverse transcriptase-polymerase chain reaction with degenerate primers specific for gamma-aminobutyric acid transporter/NET nor autoradiographic experiments with [(125)I]3b-(4-iodophenyl)-tropane-2b-carboxylic acid methyl ester revealed an additional catecholamine transporter in the medaka brain. Uptake experiments with medaka brain synaptosomes show an endogenous transport with a pharmacological profile identical to that of the recombinant meNET. Thus, meNET is probably the predominant--if not the only--catecholamine transporter in the medaka fish brain. In view of the highly conserved primary structures and pharmacological properties of meNET, it is tempting to speculate that a specific dopamine transport developed later in vertebrate evolution and probably accompanied the tremendous enlargement of the meso-telencephalic dopaminergic pathways in amniotes.
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PMID:A Na(+)/Cl(-)-dependent transporter for catecholamines, identified as a norepinephrine transporter, is expressed in the brain of the teleost fish medaka (Oryzias latipes). 1150 76

Monitoring the release and uptake of catecholamines from terminals in weakly innervated brain regions is an important step in understanding their importance in normal brain function. To that end, we have labeled brain slices from transgenic mice that synthesize placental alkaline phosphatase (PLAP) on neurons containing tyrosine hydroxylase with antibody-fluorochrome conjugate, PLAP-Cy5. Excitation of the fluorochrome enables catecholamine neurons to be visualized in living tissue. Immunohistochemical fluorescence with antibodies to tyrosine hydroxylase and dopamine beta-hydroxylase revealed that the PLAP labeling was specific to catecholamine neurons. In the prefrontal cortex (PFC), immunohistochemical fluorescence of the PLAP along with staining for dopamine transporter (DAT) and norepinephrine transporter (NET) revealed that all three exhibit remarkable spatial overlap. Fluorescence from the PLAP antibody was used to position carbon-fiber microelectrodes adjacent to catecholamine neurons in the PFC. Following incubation with L-DOPA, catecholamine release and subsequent uptake was measured and the effect of uptake inhibitors examined. Release and uptake in NET and DAT knockout mice were also monitored. Uptake rates in the cingulate and prelimbic cortex are so slow that catecholamines can exist in the extracellular fluid for sufficient time to travel approximately 100 microm. The results support heterologous uptake of catecholamines and volume transmission in the PFC of mice.
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PMID:Catecholamine release and uptake in the mouse prefrontal cortex. 1159 65

In the female rabbit, coitus induces a massive release of hypothalamic gonadotropin-releasing hormone (GnRH) within 20 min. The GnRH surge is preceded by an increase in hypothalamic norepinephrine (NE) release. Presumably, coitus stimulates NE, hence GnRH, release by increasing the activity of tyrosine hydroxylase (TH, the rate-limiting enzyme for NE synthesis) and/or decreasing the activity of norepinephrine transporter (NET, the key protein for NE re-uptake). Since NE cell bodies are located primarily in the brainstem, we hypothesize that coital signals are relayed to hypothalamic GnRH-secreting neurons via brainstem NE-containing perikarya. In support of this hypothesis, we found that both c-fos and TH mRNA expressions in brainstem noradrenergic areas, particularly in the A1 and A2 cell groups, increased within 30 min and returned to precoital levels within 60 min after coitus. Here we analyzed coitally induced changes in NET mRNA expression at 0, 15, 30 and 60 min postcoitus in the brainstem by in situ hybridization, using 35S-labeled rabbit NET RNA probes. In comparison with nonmated females (i.e., at 0 min), the expression of NET mRNA significantly increased (P<0.05) within 15 min postcoitus in the A1, but not the A2 area. By 30 min postcoitus, NET gene expression increased in the caudal portion of the A1 and in the caudal and central portion of the A2. By 60 min postcoitus, NET mRNA expression in the caudal and rostral portion of the A1 and the caudal and central portion of the A2 was still higher than NET mRNA expression in nonmated rabbits (P<0.05). No change in NET mRNA expression was observed in the A6. The results suggest that coitus increases NET mRNA expression in A1 and A2 noradrenergic areas within 15-30 min, and this enhanced NET mRNA expression was maintained for at least 60 min, particularly in the A2. These findings, in combination with our previous observation on increased TH gene expression within 30 min, but not 60 min, after coitus, further suggest that the coitus-induced NET transcriptional events within brainstem NE neurons may play an important role in the maintenance, and particularly in the termination, of hypothalamic NE release, hence regulating the size and duration of the coitus-induced GnRH surge.
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PMID:Norepinephrine transporter mRNA expression after coitus in the rabbit brainstem. 1176 82

The neurotransmitter norepinephrine has been the focus of intense investigation for nearly a century. With advances in technology come novel approaches for testing hypotheses about the physiological roles of norepinephrine and the genes involved in norepinephrine (NE) biosynthesis, metabolism, and noradrenergic signaling. Homologous recombination techniques, which generate mice deficient in specific gene products, aid the integrated physiologist and pharmacologist in the evaluation of protein function. Mouse models lacking proteins involved in NE biosynthesis or metabolism provide tools to expand the knowledge previously gleaned from pharmacologic studies. Removal of the biosynthetic enzymes tyrosine hydroxylase and dopamine-beta-hydroxylase yield animals deficient in norepinephrine and have been used to further examine the role of NE in diverse physiologic roles. Complete removal of the vesicular monoamine transporter has demonstrated that mobilizing neurotransmitters to vesicles is required for animal survival. Lastly, the generation of animals in which the ability to remove NE from the synapse is impaired (norepinephrine transporter deficiency and extraneuronal monoamine transporter deficiency) and in which the enzymes responsible for the metabolism of NE have been removed (catechol-O-methyltransferase and monoamine oxidase) has facilitated the study of the long-term physiological consequences of altered NE homeostasis.
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PMID:Genetic manipulation of noradrenergic neurons. 1196 Oct 38

The norepinephrine transporter (NET) regulates adrenoreceptor signaling by controlling the availability of synaptic norepinephrine (NE), and it is a direct target for some classes of antidepressant drugs. NET levels are normal in dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack NE, demonstrating that the NET does not require endogenous NE for appropriate regulation under physiological conditions. In contrast, tyrosine hydroxylase knockout (Th -/-) mice that lack both NE and dopamine (DA) have reduced levels of NET, suggesting that it is down-regulated by a complete absence of catecholamines and not NE per se. Chronic treatment with the NET inhibitor, desipramine (DMI), reduced NET levels in both control and Dbh -/- mice, demonstrating that NE is not required for the regulation of NET by antidepressant drugs. There are some qualitative and quantitative differences in the down-regulation of the NET by catecholamine depletion and DMI treatment, suggesting that different mechanisms may be involved.
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PMID:Regulation of norepinephrine transporter abundance by catecholamines and desipramine in vivo. 1213 27

Since estrogen exerts wide ranging effects within the central nervous system, it is important to investigate the sites and actions of this gonadal steroid hormone at extra-hypothalamic locations. In the present report, the effects of estrogen upon catecholaminergic function within the olfactory bulb were examined. To assess the role of estrogen at this site, ovariectomized mice received either no further hormonal treatment or were treated with estrogen, the anti-estrogen, tamoxifen, or a combination of estrogen and tamoxifen as administered in a 21-day release pellet. At 14 days post-hormonal treatment, the olfactory bulbs were assayed for mRNA levels of tyrosine hydroxylase, dopamine transporter and norepinephrine transporter using competitive-PCR. Tyrosine hydroxylase mRNA levels in either estrogen or estrogen+tamoxifen treated females were significantly decreased compared with non-hormonally treated controls. In addition, tyrosine hydroxylase mRNA levels of tamoxifen-treated mice were significantly greater than that of estrogen-treated mice. Dopamine transporter mRNA levels of tamoxifen-treated females were significantly greater than that of non-hormonally treated controls and estrogen treated mice. The combination of estrogen+tamoxifen significantly increased dopamine transporter mRNA levels compared to that of estrogen treated mice. No overall statistically significant differences in norepinephrine transporter mRNA levels were obtained among the four treatment groups. The data demonstrate that estrogen can exert significant modulatory effects upon olfactory bulb catecholaminergic function. Therefore, events which alter estrogen levels (menstrual/estrogen cycle, pregnancy/lactation, menopause, tamoxifen treatment) can modulate olfactory bulb catecholaminergic functions which may be involved with the detection and processing of olfactory stimuli.
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PMID:Modulation of olfactory bulb tyrosine hydroxylase and catecholamine transporter mRNA by estrogen. 1248 Jan 84

In females, sympathetic activity varies with changes in reproductive status, but whether expression of proteins critical to the function of sympathetic neurons is also altered is unknown. Therefore, the present study tested the hypothesis that, in rat adrenal gland and superior cervical ganglia, the expression of tyrosine hydroxylase (TH) and the norepinephrine transporter (NET), measured using Western analysis, are changed during pregnancy and the estrous cycle. Compared to diestrus, pregnancy increased TH levels in both superior cervical ganglia and adrenal gland. Pregnancy was also associated with decreased NET levels in the superior cervical ganglia, but increased levels in the adrenal gland. Relative to diestrus, the pattern of changes of TH and the NET in rats during proestrus was generally similar to changes observed during pregnancy. To assess whether gonadal hormones were involved, ovariectomized rats were also studied and changes in serum estrogen and progesterone were assayed in a subset of animals in all groups. Variations in TH and the NET among all groups did not correlate with changes in either estrogen or progesterone, suggesting that the steroids were not exclusively responsible. In conclusion, reproductive status alters the expression of TH and the NET in adrenal gland and superior cervical ganglia of female rats, which could significantly influence the function of the sympathetic nervous system. However, the mechanism for these changes does not depend solely on changes in estrogen or progesterone.
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PMID:Tyrosine hydroxylase and norepinephrine transporter in sympathetic ganglia of female rats vary with reproductive state. 1274 86

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