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)

We examined the mechanism of the inhibitory effect of prostanoid EP(3) receptor agonists on naloxone-precipitated withdrawal syndrome in morphine-dependent rats. Rats were rendered morphine dependent by subcutaneous (s.c.) implantation of two pellets containing 75 mg morphine for 5 days. Morphine withdrawal syndrome was precipitated by i.p. injection of naloxone (3 mg/kg). Intracerebroventricular (i.c.v.) administration of (+/-)-15alpha-hydroxy-9-oxo-16-phenoxy-17,18, 19,20-tetranorprost-13-trans-enoic acid (M&B28,767: prostanoid EP(3) receptor agonist) or sulprostone (prostanoid EP(1)/EP(3) receptor agonist) significantly suppressed many withdrawal signs. Northern blotting and in situ hybridization studies revealed that i.c.v. administration of M&B28,767 (1 pg/rat) attenuated the elevation of c-fos mRNA during naloxone-precipitated withdrawal in many brain regions, including the cerebral cortex, thalamus, hypothalamus and locus coeruleus. Double in situ hybridization analysis revealed that in the locus coeruleus most of the tyrosine hydroxylase mRNA-positive neurons expressed mu-opioid receptor mRNA and more than half of these neurons were positive for prostanoid EP(3) receptor mRNA. These results indicate that the suppression by prostanoid EP(3) receptor agonists of naloxone-precipitated morphine withdrawal syndrome can be attributed to the inhibition of neuronal activity in several brain regions, including the locus coeruleus, the largest source of central noradrenergic neurons.
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PMID:Possible involvement of the locus coeruleus in inhibition by prostanoid EP(3) receptor-selective agonists of morphine withdrawal syndrome in rats. 1070 32

Several studies have demonstrated that behavioral activation induced by psychostimulants is prevented by ginseng total saponin (GTS), which has been known to act on the central dopaminergic system. In an attempt to investigate whether the effect of GTS is through its inhibitory action on the elevated dopaminergic transmission, we examined the effect of GTS on nicotine-induced dopamine (DA) release in the nucleus accumbens (NA) of freely moving rats using in vivo microdialysis. Systemic injection of nicotine (3 mg/kg; i.p.) produced a mild increase in extracellular DA of dialysates samples in the NA (132+/-13% over basal levels at the peak). GTS (100 mg/kg; i.p.) had no effect on resting levels of extracelluar DA. However, an increase in accumbens DA release produced by systemic nicotine was completely blocked by systemic pre-treatment with GTS (100 mg/kg; i.p.). In addition, the effect of GTS on nicotine-induced tyrosine hydroxylase (TH) and immediate early gene expression in ventral tegmental area (VTA) or NA regions was examined. A single injection of nicotine increased TH mRNA level at VTA region. GTS, which did not affect the basal TH mRNA expression, attenuated nicotine-induced TH mRNA expression. Nicotine slightly increased both c-fos and c-jun mRNA level and GTS, which did not affect the basal c-fos and c-jun mRNA expression, further enhanced nicotine-induced c-fos and c-jun mRNA level at both VTA and NA regions. Our results suggest that GTS may have an inhibitory action against nicotine-induced DA release in NA region and TH mRNA expression in VTA region. GTS may exert an potentiative effect on both c-fos and c-jun mRNA expression at NA region through inhibiting the release of DA in NA.
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PMID:Modulatory effect of ginseng total saponin on dopamine release and tyrosine hydroxylase gene expression induced by nicotine in the rat. 1077 Dec 6

Our previous studies indicate that coitus in female rabbits induces a gonadotropin-releasing hormone (GnRH) surge that is preceded by an increase in hypothalamic norepinephrine (NE) release. The additional findings of an enhanced tyrosine hydroxylase (TH) mRNA expression in the female brainstem after coitus, in addition to the appropriate topographic distribution of TH and dopamine-beta-hydroxylase (DBH), lead us to hypothesize that coital signals are relayed to hypothalamic GnRH-secreting neurons via brainstem NE-containing perikarya. Here we analyzed coitally activated areas in the brainstem by in situ hybridization of the oncogene c-fos, as well as the expression of TH mRNA at 0, 30 and 60 min postcoitus using specific 35S-labeled probes for c-fos and TH. To establish the identity of activated brainstem neurons, we immunocytochemically double-labeled cells with specific antibodies against Fos protein and DBH at 90 min postcoitus. Both c-fos and TH mRNAs were present at 0 min (control) in the A1, A2 and A6 brainstem-noradrenergic areas. At 30 min after coitus the expression of both genes significantly increased (P<0.01) in the A1 and A2 areas. By 60 min postcoitus the expression of c-fos mRNA decreased to control levels, while that of TH mRNA remained stimulated. Double-labeling of Fos and DBH indicated that the number of dual-labeled neurons increased (P<0.05) over control levels only in the A1 and A2 areas (not in A6) at 90 min postcoitus. These findings support the hypothesis that coitus activates transcriptional/translational events within brainstem NE neurons that culminate in the release of hypothalamic NE and hence a GnRH surge.
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PMID:Molecular activation of noradrenergic neurons in the rabbit brainstem after coitus. 1083 17

Dopamine-deficient (DA-/-) mice were created by targeted inactivation of the tyrosine hydroxylase gene in dopaminergic neurons. The locomotor activity response of these mutants to dopamine D1 or D2 receptor agonists and l-3,4-dihydroxyphenylalanine (l-DOPA) was 3- to 13-fold greater than the response elicited from wild-type mice. The enhanced sensitivity of DA-/- mice to agonists was independent of changes in steady-state levels of dopamine receptors and the presynaptic dopamine transporter as measured by ligand binding. The acute behavioral response of DA-/- mice to a dopamine D1 receptor agonist was correlated with c-fos induction in the striatum, a brain nucleus that receives dense dopaminergic input. Chronic replacement of dopamine to DA-/- mice by repeated l-DOPA administration over 4 d relieved the hypersensitivity of DA-/- mutants in terms of induction of both locomotion and striatal c-fos expression. The results suggest that the chronic presence of dopaminergic neurotransmission is required to dampen the intracellular signaling response of striatal neurons.
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PMID:Dopamine-deficient mice are hypersensitive to dopamine receptor agonists. 1084 9

Organisms respond to hypoxia through detection of blood oxygen levels by sensors at peripheral chemoreceptors and by receptors in certain key cells of the body. The pathways over which peripheral chemoreceptor signals are transmitted to respiratory muscles are well established. However, the intracellular pathways that transmit hypoxic stimulus to gene activation are just being identified. Using anti-sense c-fos strategy, we have shown that c-fos is essential for the activation of activator protein-1 transcription factor complex (AP-1) and subsequent stimulation of downstream genes such as tyrosine hydroxylase (TH; Mishra et al. 1998). The purpose of the present study was to identify intracellular pathways that link hypoxia to activation of c-fos. The results of the present study show that hypoxia causes Ca2+ influx through L-type voltage gated Ca2+ channels and that hypoxia-induced c-fos gene expression is Ca2+/calmodulin dependent. We also demonstrate that hypoxia activates the extracellular-regulated kinase (ERK) and p38, but not JNK. Further, phosphorylation of ERK is essential for c-fos activation via SRE cis-element. Further characterization of nuclear signalling pathways provides evidence for the involvement of Src, a non receptor protein tyrosine kinase, and Ras, a small G protein, in the hypoxia-induced c-fos gene expression. These results suggest a possible role for non-receptor protein tyrosine kinases in propagating signals from G-protein coupled receptors to the activation of immediate early genes such as c-fos during hypoxia.
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PMID:Intracellular pathways linking hypoxia to activation of c-fos and AP-1. 1084 52

It is being increasingly recognized that nitric oxide (NO) is associated with many physiological processes, including regulation of gene expression. NO shares certain similarities with molecular oxygen (O2). Previous studies have shown that hypoxia up-regulates c-fos, an immediate early gene, and tyrosine hydroxylase (TH), a late response gene that encodes rate limiting enzyme in catecholamine synthesis. Given the similarities between NO and O2, we hypothesized that NO inhibits hypoxia-induced up-regulation of c-fos and TH. Experiments were performed on rat pheochromocytoma (PC12) cells. c-fos and TH mRNA's were analysed by Northern blot and promoter activities by reporter gene assays, respectively. Hypoxia (1% O2 for 6 h) up-regulated c-fos and TH mRNA and increased c-fos promoter activity. Hypoxia-induced c-fos mRNA expression, and promoter activities were significantly potentiated in presence of spermine nitric oxide (SNO), a NO donor. By contrast, SNO significantly inhibited TH mRNA expression and TH promoter activity during hypoxia. Electrophoretic mobility shift-assay showed increased binding of AP-1 and HIF-1 transcription factors to the TH promoter in cells exposed to hypoxia. SNO abolished the binding of AP-1 and HIF-1 to the TH promoter during hypoxia, suggesting that inhibition of hypoxia-induced TH transcription by NO are due to reduced binding of AP-1 and HIF-1 transcription factors. These result demonstrate that NO has both positive and negative influence on gene regulation by hypoxia and suggest that although NO resembles O2 does not always inhibit gene expression during low oxygen.
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PMID:Dual influence of nitric oxide on gene regulation during hypoxia. 1084 69

The precise mechanisms by which beneficial responses to acute stress are transformed into long-term pathological effects of chronic stress are largely unknown. Western blot analyses revealed that members of the AP1 transcription factor family are differentially regulated by single and repeated stress in the rat adrenal medulla, suggesting distinct roles in establishing stress-induced patterns of gene expression in this tissue. The induction of c-fos was transient, whereas marked elevation of long-lasting Fos-related antigens, including Fra2, was observed after repeated immobilization. We investigated DNA protein interactions at the AP1-like promoter elements of two stress-responsive genes, tyrosine hydroxylase and dopamine beta-hydroxylase. Increased DNA-binding activity was displayed in adrenomedullary extract from repeatedly stressed rats, which was predominantly composed of c-Jun- and Fra2-containing dimers. The induction of Fra2 and increased AP1-like binding activity was reflected in sustained transcriptional activation of tyrosine hydroxylase and dopamine beta-hydroxylase genes after repeated episodes of stress. The functional link between Fra2 and regulation of tyrosine hydroxylase and dopamine beta-hydroxylase transcription was confirmed in PC12 cells coexpressing this factor and the corresponding promoter-reporter gene constructs. These studies emphasize the potential importance of stress-evoked increases in the expression of the Fra2 gene for in vivo adaptations of the adrenal catecholamine producing system.
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PMID:Fos-related antigen 2: potential mediator of the transcriptional activation in rat adrenal medulla evoked by repeated immobilization stress. 1090 2

Brainstem noradrenergic neurons, particularly the locus-coeruleus (LC), play a pivotal role in modulating the central stress response and have been implicated in regulating the hypothalamic-pituitary-adrenal (HPA) axis. In adult rats, acute stress causes an increase in LC firing and tyrosine hydroxylase (TH) gene expression. While the role of the LC-norepinephrine (LC-NE) system in the adult stress response has been well characterized, there is limited evidence for its participation during development. Previous studies described the neonatal HPA axis as hyporeactive because of stimulus-selective pituitary activation. However, maternal deprivation does reinstate stress-induced endocrine activity and can amplify the neural stress response. Considering that LC neurons can modulate neuroendocrine activity, we hypothesized that the LC-NE system would be stress-responsive during development. Because maternal deprivation (DEP) can alter the central stress response, we examined the LC-NE stress response in both DEP and non-deprived (NDEP) pups. Following an isotonic saline injection (stressor) the time course of TH, c-fos and glucocorticoid receptor (GR) mRNA was examined. Stress-induced TH mRNA was increased in DEP pups at postnatal day (pnd) 12 and in both NDEP and DEP pups at pnd 18. At 15, 30 and 240 min c-fos mRNA was markedly increased in all groups examined. GR mRNA was not altered at pnd 12; however, at pnd 18 NDEP pups showed reduced GR mRNA expression. These data indicate that during ontogeny the LC-NE system is stress-responsive to an acute mild challenge. Activation of LC-NE neurons suggests that this system may participate in modulating the neuroendocrine stress response during development.
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PMID:Stress-induced alterations in locus coeruleus gene expression during ontogeny. 1128 61

The interaction of cholinergic and catecholaminergic mechanisms in the mesopontine region has been hypothesized as being critical for the generation and maintenance of active (REM) sleep. To further examine this hypothesis, we sought to determine the pattern of neuronal activation (via c-fos expression) of catecholaminergic and cholinergic neurons in this region during active sleep induced by the pontine microapplication of carbachol (designated as active sleep-carbachol). Accordingly, we used two sets of double-labeling techniques; the first to identify tyrosine hydroxylase-containing neurons (putative catecholaminergic cells) which also express the c-fos protein product Fos, and the second to reveal choline acetyltransferase-containing neurons (putative cholinergic cells) which also express Fos. Compared to control cats, active sleep-carbachol cats exhibited a significantly greater number of Fos-expressing neurons in the dorsolateral region of the pons, which encompasses the locus coeruleus, the lateral pontine reticular formation, the peribrachial nuclei and the latero-dorsal and pedunculo-pontine tegmental nuclei. However, both control and active sleep-carbachol cats exhibited a similar number of catecholaminergic and cholinergic neurons in those regions that expressed Fos (i.e., double-labeled cells). A large number of c-fos-expressing neurons in the active sleep-carbachol cats whose neurotransmitter phenotype was not identified suggests that non-catecholaminergic, non-cholinergic neuronal populations in mesopontine regions are involved in the generation and maintenance of active sleep. The lack of increased c-fos expression in catecholaminergic neurons during active sleep-carbachol confirms and extends previous data that indicate that these cells are silent during active sleep-carbachol and naturally-occurring active sleep. The finding that cholinergic neurons of the dorsolateral pons were not activated either during wakefulness or active sleep-carbachol raises questions regarding the synaptic mechanisms of activation of these cells during these behavioral states.
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PMID:c-fos Expression in mesopontine noradrenergic and cholinergic neurons of the cat during carbachol-induced active sleep: a double-labeling study. 1138 55

We investigated whether single injection of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) (20 mg/kg) will alter the expression of pro-apoptotic genes, namely, the c-fos, c-jun, and bax, in the striatum, cortex, and cerebellum of adult male C57BL/6 mice using reverse transcription-polymerase chain reaction assay. Injection of MPTP induced a transient decrease in the content of tyrosine hydroxylase estimated by the immunoreactivity in the striatum, which completely recovered 14 day after injection. A rapid but transient up-regulation of c-fos and c-jun genes occurred an hour after MPTP-injection, and a delayed but persistent up-regulation of bax gene expression occurred 3 day after injection. The up-regulation of these genes was present in all the examined brain regions. This result suggests that MPTP, at a low dose causing transient degeneration in the striatum, is capable of triggering two genetic pathways related to the generation of apoptosis in both dopaminergic and non-dopaminergic systems in the mouse brain.
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PMID:Sequential up-regulation of the c-fos, c-jun and bax genes in the cortex, striatum and cerebellum induced by a single injection of a low dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57BL/6 mice. 1169 44


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