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)

Ras is a universal eukaryotic intracellular protein integrating extracellular signals from multiple receptor types. To investigate its role in the adult central nervous system, constitutively activated V12-Ha-Ras was expressed selectively in neurons of transgenic mice via a synapsin promoter. Ras-transgene protein expression increased postnatally, reaching a four- to fivefold elevation at day 40 and persisting at this level, thereafter. Neuronal Ras was constitutively active and a corresponding activating phosphorylation of mitogen-activated kinase was observed, but there were no changes in the activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-X(L). Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression. Degeneration of motorneurons was completely prevented after facial nerve lesion in Ras-transgenic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic substantia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers neuroprotective mechanisms in adult mice. Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.
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PMID:Transgenic activation of Ras in neurons promotes hypertrophy and protects from lesion-induced degeneration. 1113 81

Portal hypertension due to either prehepatic portal hypertension or cirrhosis is associated with cardiovascular derangement. We aimed to delineate regulatory mechanisms in the brain stem cardiovascular nuclei in rat models of prehepatic portal hypertension and cirrhosis. Neuronal activation in the nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM) were assessed by immunohistochemical staining for the immediate-early gene product Fos. In the same sections, catecholaminergic neurons were counted by tyrosine hydroxylase (TH) staining. Ninety minutes after hypotensive hemorrhage (or no volume challenge), the animals were killed for Fos and TH medullary staining. These protocols were repeated after capsaicin administration. The NTS of unchallenged sham-operated rats had scant Fos-positive cells (3.6 +/- 0.4 cells/section), whereas hemorrhage significantly increased Fos staining (91.8 +/- 14). In contrast, the unchallenged portal hypertensive and cirrhotic groups showed increased Fos staining (14.3 +/- 5.8 and 32.8 +/- 2.8, respectively), which hemorrhage did not alter significantly. The numbers of TH-positive cells were similar in the three unchallenged groups; double labeling revealed that approximately 50% of TH-positive cells were activated by hemorrhage in the sham and cirrhotic rats but not the portal hypertensive rats. Similar patterns of Fos and TH staining were observed in the VLM. Capsaicin treatment not only significantly reduced the Fos-positive neuron numbers in portal hypertensive and cirrhotic rats but also attenuated hemorrhage-induced Fos and double-positive cells in both NTS and VLM. These results suggest that disordered trafficking in capsaicin-sensitive nerves and central dysregulation contribute to blunted cardiovascular responsiveness in cirrhosis and prehepatic portal hypertension.
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PMID:Disordered central cardiovascular regulation in portal hypertensive and cirrhotic rats. 1117 24

1. In normal mice, the distribution of adrenergic, cholinergic, some peptidergic, and neuronal nitric oxide synthase (nNOS)-containing nerves were investigated. Functional in vitro correlates were obtained. An in vivo model was developed in which erectile haemodynamics in response to drugs or nerve-stimulation were studied. 2. Immunoreactivities for vesicular acetylcholine transporter protein (VAChT), nNOS-, and vasoactive intestinal polypeptide (VIP), co-existed in nerve fibres and terminal varicosities. Immunoreactivities for neuropeptide Y (NPY) and tyrosine hydroxylase (TH) were found in the same nerve structures. 3. Chemical sympathectomy abolished TH- and NPY-IR nerve structures in cavernous smooth muscle bundles. The distribution of calcitonin gene-related peptide (CGRP)-, nNOS-, VAChT- and VIP-IR nerve structures was unchanged. 4. In endothelial cells of the central and helicine arteries, veins and venules, intense immunoreactivity for endothelial NOS (eNOS) was observed. No distinct eNOS-IR cells were found lining the cavernous sinusoids. 5. In vitro, nerve-induced relaxations were verified, and endothelial NO/cyclic GMP-mediated relaxant responses were established. VIP and CGRP had small relaxant effects. A functioning adenylate cyclase/cyclic AMP pathway was confirmed. 6. Neuronal excitatory responses were abolished by prazosin, or forskolin. VIP and CGRP counteracted contractions, whereas NPY and scopolamine enhanced excitatory responses. 7. In vivo, erectile responses were significantly attenuated by L-NAME (50 mg kg(-1)) and facilitated by sildenafil (200 microg kg(-1)). 8. It is concluded that the mouse is a suitable model for studies of erectile mechanisms in vitro and in vivo.
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PMID:Morphological and functional in vitro and in vivo characterization of the mouse corpus cavernosum. 1125 Aug 85

Neuronal nicotinic acetylcholine receptors (nAChRs) play a significant role in sympathetic transmission in the superior cervical ganglia (SCG), with most of the signal carried by a nAChR containing an alpha3 subunit. Work has shown that transection of the postganglionic nerves (axotomy) of the SCG results in a decrease in mRNA transcripts for alpha3, alpha5, alpha7 and beta4 and in protein expression of alpha7 and beta4. To evaluate effects of axotomy on alpha3 protein in the SCG, quantitative immunoblotting was used to demonstrate a dramatic decrease (> 80%) in the levels of this subunit 4 days after axotomy. Similarly, immunocytochemistry showed a marked decline in the number and the intensity of stained neurons for the alpha3 subunit as well as tyrosine hydroxylase. Ganglia explanted into culture for 4 days also showed a substantial decrease in alpha3 subunit protein. This decrease was partially prevented by the addition of nerve growth factor (NGF) to the culture medium at the time of explantation. Additionally, this decrease was reversed by the addition of NGF to the culture medium following 4 days in culture in the absence of NGF. These findings suggest that the loss of alpha3 subunit contributes to the reported decrease in ganglionic synaptic transmission that follows axotomy, and that NGF plays an important role in regulating the expression of alpha3-containing nAChRs in the SCG.
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PMID:Axotomy and nerve growth factor regulate levels of neuronal nicotinic acetylcholine receptor alpha3 subunit protein in the rat superior cervical ganglion. 1167 53

We compared tyrosine hydroxylase immunoreactivity in the substantia nigra and hypothalamus of hereditary microphthalmic rats with that of normal rats. A considerable number of neuronal cell bodies expressing tyrosine hydroxylase were present in the substantia nigra of the microphthalmic mutant as well as normal rats. Neuronal cells positive for tyrosine hydroxylase in the hypothalamus were fewer than in the substantia nigra in both rats. The concentrations of monoamines (dopamine, noradrenaline, adrenaline, and serotonin) in the substantia nigra and hypothalamus in the microphthalmic mutant were approximately the same as those of normal rats, although the diurnal fluctuation of a few monoamines was observed in normal rats. These results suggest that the metabolic aspects of catecholamine in the substantia nigra and hypothalamus of the microphthalmic mutant rat do not markedly differ from those of normal rats.
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PMID:Immunohistochemical detection of tyrosine hydroxylase and concentrations of monoamines in the substantia nigra and hypothalamus of hereditary microphthalmic rats. 1176 50

Electrophysiologic recording and indirect immunofluorescence were combined to study localization of the medium-sized neurofilament 145 (NF145) component of the cytoskeleton in morphologically identified neurons in the myenteric and submucosal plexuses of the guinea pig enteric nervous system. Neuronal localization of chemical markers, including calbindin DK28, calretinin, nitric oxide synthase, choline-acetyltransferase, neuropeptide Y, serotonin, neurokinin 1 receptor protein, and somatostatin, was integrated with electrophysiologic and morphologic results for a more complete assessment. NF145 immunoreactivity (-IR) was present in ganglion cells with Dogiel type I morphology in the myenteric plexus of the stomach and small and large intestine. NF145-IR was not found in myenteric ganglion cells with Dogiel type II morphology. NF145-IR was not present in any of the ganglion cells in the submucosal plexus. NF145 was expressed in nerve fibers in both myenteric and submucosal plexuses. The majority of these fibers were identified as sympathetic postganglionic axons based on their disappearance in organotypic culture and on their expression of tyrosine hydroxylase. The myenteric ganglion cells with NF145-IR had electrophysiologic properties of S-type enteric neurons. NF145-IR was found in neurons with vasoactive intestinal peptide, serotonin, nitric oxide synthase, somatostatin, and neurokinin 1 receptor but not with neuropeptide Y or calbindin. The results in general suggest that NF145 is localized to distinct subsets of myenteric motor neurons and interneurons. Absence of NF145 from ganglion cells in the submucosal plexus is an example of differences between myenteric and submucosal components of the enteric nervous system.
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PMID:Chemical coding and electrophysiology of enteric neurons expressing neurofilament 145 in guinea pig gastrointestinal tract. 1177 35

Oxytocin is synthesized by magnocellular neurons in the supraoptic and paraventricular nuclei (SON and PVN) and during pregnancy progesterone prevents premature activation of oxytocin neurons. Progesterone receptors (PR) are not detectable in SON oxytocin neurons of non-pregnant rats, so we sought to determine whether they are expressed during pregnancy and parturition. In addition, we examined PR expression in brainstem and hypothalamic regions that have known direct projections to the SON. Neuronal immunoreactive PR (irPR)-labeled nuclei were counted in sections from proestrous virgin, late pregnant (day 21) and parturient rats (90 min from birth onset). IrPR nuclei were not evident in the SON at any stage but irPR expression in the medial preoptic nucleus (MPA) significantly increased in pregnancy and parturition (159% and 189% of proestrous controls, respectively). Other hypothalamic areas did not exhibit a significant change in irPR expression. In the nucleus tractus solitarius (NTS) in the brainstem, there was no significant change in irPR in late pregnancy, but there was a significant reduction in irPR expression at parturition (22% of proestrous controls). Very few NTS neurons immunoreactive for tyrosine hydroxylase (irTH), and thus putatively noradrenergic, contained irPR. These findings taken with evidence that brainstem irTH neurons projecting to the SON are stimulated at parturition, whereas MPA cells projecting to the SON are not, suggest that any direct actions of progesterone or progesterone withdrawal on NTS or SON neurons are not mediated through the classical PR. Upregulation of PR expression in the MPA during pregnancy and parturition may relate to the onset of maternal behavior and/or regulation of GnRH neuronal activity.
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PMID:Progesterone receptor expression in the pregnant and parturient rat hypothalamus and brainstem. 1181 28

To assess whether diabetes alters the content and/or expression of neuroactive agents and protooncogenes in afferent neurons of the vagus nerve, the nodose ganglia of streptozotocin (STZ)-induced diabetic rats were studied at 8, 16, and 24 weeks after induction of diabetes. Neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase (TH), the immediate early gene c-Jun, vasoactive intestinal peptide (VIP) and calcitonin gene related peptide (CGRP) content and expression were measured in nodose ganglia of control, diabetic, and diabetic+insulin-treated rats using immunocytochemistry and reverse transcription-polymerase chain reaction (RT-PCR). The numbers of nNOS-immunoreactive (ir) neurons were increased in the nodose ganglion of diabetic compared to control rats at the 8- and 16-week time points. However, no change was noted in the nNOS mRNA content of the diabetic nodose ganglion at either time point. Moreover, no alterations in the numbers of vagal efferent NOS-containing neurons (labeled with NADPH-diaphorase histochemistry) were noted in the dorsal motor nucleus of the vagus (DMV) or the nucleus ambiguous (NA) of control, diabetic, and diabetic+insulin-treated rats at any time point. Neither the numbers of TH-ir neurons nor the content of TH mRNA was altered in the diabetic rats at the 8- and 16-week time points. However, 24 weeks of diabetes resulted in a reduction in the numbers of TH-ir neurons in the diabetic nodose ganglia when compared to control, an effect not seen in diabetic rats receiving insulin. The number of nodose ganglion neurons labeled for the protooncogene, c-Jun, was small yet slightly increased in the diabetic nodose ganglia at the 8-week time point and was reversed with insulin treatment. The increase in c-Jun-ir neurons was not found at 16 or 24 weeks of diabetes. VIP-ir and CGRP-ir were unchanged at any of the time points. These data show that diabetes affects the content of some, but not all, neuroactive agents in the nodose ganglion and may reflect a modest level of diabetes-induced damage and/or alterations in axonal transport in the vagus nerve.
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PMID:Streptozotocin-induced diabetes and the neurochemistry of vagal afferent neurons. 1203 29

Neuronal activation of brain vagal-regulatory nuclei and gastric/duodenal enteric plexuses in response to insulin (2 U/kg, 2 h) hypoglycemia was studied in rats. Insulin hypoglycemia significantly induced Fos expression in the paraventricular nucleus of the hypothalamus, locus coeruleus, dorsal motor nucleus of the vagus (DMN), and nucleus tractus solitarii (NTS), as well as in the gastric/duodenal myenteric/submucosal plexuses. A substantial number of insulin hypoglycemia-activated DMN and NTS neurons were choline acetyltransferase and tyrosine hydroxylase positive, respectively, whereas the activated enteric neurons included NADPH- and vasoactive intestinal peptide neurons. The numbers of Fos-positive cells in each above-named brain nucleus or in the gastric/duodenal myenteric plexus of insulin-treated rats were negatively correlated with serum glucose levels and significantly increased when glucose levels were lower than 80 mg/dl. Acute bilateral cervical vagotomy did not influence insulin hypoglycemia-induced Fos induction in the brain vagal-regulatory nuclei but completely and partially prevented this response in the gastric and duodenal enteric plexuses, respectively. These results revealed that brain-gut neurons regulating vagal outflow to the stomach/duodenum are sensitively responsive to insulin hypoglycemia.
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PMID:Neuronal activation of brain vagal-regulatory pathways and upper gut enteric plexuses by insulin hypoglycemia. 1216 36

Neuronal transplantation is considered to be a promising therapeutic approach to neurodegenerative diseases. In addition to fetal tissues and neural stem cells, embryonic stem cells are good candidates for the creation of neurons. We have recently identified a stromal cell-derived inducing activity that promotes neural differentiation of mouse embryoric stem cells. This activity accumulated on the surface of PA6 stromal cells and induced efficient neuronal differentiation of co-cultured embryonic stem cells under serum-free conditions without the use of either retinoic acid or embryoid bodies. A high proportion of tyrosine hydroxylase-positive neurons producing dopamine are obtained. Induction of neurons with stromal cell-derived inducing activity may be a useful new method for basic neuroscience research and therapeutic applications, including cell transplantation therapy for Parkinson's disease.
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PMID:Generation of dopaminergic neurons from embryonic stem cells. 1237 63


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