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)

Release properties of intrahippocampal transplants of noradrenergic neurons were monitored by microdialysis in awake and halothane-anaesthetized rats. Fetal locus coeruleus neurons were implanted as a cell suspension into hippocampi deprived of their innate noradrenalin (NA) innervation by intraventricular 6-hydroxydopamine treatment. Dialysis probes of the loop type were implanted into the dorsal hippocampus 1 - 2 days before each experiment, i.e. 7 - 11 months after grafting. Age-matched intact and lesion-only animals served as controls. Microscopic analysis showed a graft-derived tyrosine hydroxylase immunoreactive, presumably noradrenergic, fibre network throughout the dorsal hippocampal formation, surrounding the probe site. The innervation density varied from sub- to supranormal. The grafts restored baseline NA release in the graft-reinnervated hippocampus to near-normal levels both in awake and halothane-anaesthetized animals. Potassium chloride (100 mM) in the perfusion fluid induced a dramatic increase in NA release that was similar in magnitude in the grafted and intact hippocampi. A NA uptake blocker (desipramine) added to the perfusion fluid at 5 microM induced a similar increase in NA output in the grafted and intact hippocampi, and the output was substantially reduced by tetrodotoxin, added at 1 microM in the presence of uptake blockade. Electrical stimulation of the lateral habenular nucleus (15 Hz, 0.5 mA) in halothane-anaesthetized rats induced a significant increase in NA output both in the intact and grafted hippocampi. This effect was abolished by transection of the fasciculus retroflexus, which carries the efferent projections of the habenular complex. Behavioural activation through handling induced a consistent increase in NA release only in the intact animals, but in a few grafted rats (which also responded to habenular stimulation) the NA output was clearly elevated by handling. Forced immobilization induced a significant increase in NA output both in the intact and grafted hippocampi, but in the grafted ones the response was somewhat smaller and more transient. In the same set of animals, swimming in warm water (25 - 30 degrees C) induced a sharp increase in NA output in the intact animals, whereas only one of the grafted rats responded by increased NA output. The results indicate that the locus coeruleus grafts, despite their ectopic location, can become functionally integrated with the host brain, and that the activity of the transplanted noradrenergic neurons can, under some circumstances, be modulated from the host brain in response to environmental challenges.
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PMID:Host Brain Regulation of Fetal Locus Coeruleus Neurons Grafted to the Hippocampus in 6-Hydroxydopamine-Treated Rats. An Intracerebral Microdialysis Study. 1210 57

Antipsychotic drugs (APD) are used in the treatment of schizophrenia and other psychotic disorders and exert their effects, in part, through dopamine receptor blockade. APD treatment causes many changes in the brains of humans and experimental animals including therapeutic, pathologic, or changes associated with motor side effects. Typical APD given chronically to animals induce behavioral sequelae that mimic tardive dyskinesia in several ways. Our previous work has shown that chronic treatment with haloperidol decreases striatal synaptic density but that symmetric synapses are lost only in rats that develop oral dyskinesias. The goals of this study were to determine if the density of dopaminergic terminals was affected by chronic haloperidol treatment and/or correlated with dyskinesias. Rats were given haloperidol (1.5 mg/kg/rat) or water, as a control. After 6 months of treatment, rats were divided into nondyskinetic or dyskinetic groups according to the behavior scores determined in the last month. Striatal volume was similar between controls and drug-treated rats. Synaptic density, calculated using stereological methods, was obtained from the matrix of the ventrolateral striatum. The density of symmetric synapses (mean +/- SD, per 100/microm(3)) formed by tyrosine hydroxylase (TH) containing terminals in haloperidol treated rats (3.58 +/- 1.64) was not significantly different from that of controls (3.06 +/- 1.00). The density of TH-labeled terminals forming symmetric synapses in the nondyskinetic group (3.65 +/- 1.67) vs. the dyskinetic group (3.54 +/- 1.73) was similar and neither was different from that of the controls. These data indicate that terminals other than dopaminergic ones form fewer symmetric synapses in dyskinetic rats. Moreover, these data have implications for interpreting results obtained in humans treated with typical antipsychotic drugs.
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PMID:Dopaminergic synapses in the matrix of the ventrolateral striatum after chronic haloperidol treatment. 1211

Previous studies have shown the existence of functional angiotensin II receptors in rat carotid body, which directly alters the carotid chemoreceptor afferent nerve activity. Moreover, chronic hypoxia could result in an enhanced sensitivity of chemoreceptor afferent activity via an AT(1) receptor-mediated calcium signaling in the carotid body. In the present study, the localization and expression of angiotensinogen, the obligatory component for an intrinsic, angiotensin-generating system, were investigated by in situ hybridization histochemistry, immunohistochemistry, RT-PCR, Western blot and Northern blot analysis. In situ hybridization showed the expression of angiotensinogen within the glomus cells of the carotid body. Double immunostaining of angiotensinogen and tyrosine hydroxylase, an immunohistochemical marker for type I glomus cells, elucidated that angiotensinogen protein was specifically localized to the lobules of type I cells. Consistently, RT-PCR and Western blot analysis confirmed the expression of angiotensinogen mRNA and protein, respectively. On the other hand, renin mRNA was not detected using RT-PCR and Northern blot analysis whereas angiotensin-converting enzyme (ACE) mRNA was detected in the carotid body. These data suggest that a locally generated angiotensin system is operated in the carotid body, which might be linked to a renin-independent biosynthetic pathway. Such an intrinsic, angiotensin-generating system and its local regulation by chronic hypoxia should be important in the modulation of cardiopulmonary adaptation in the hypoxic ventilatory response and the electrolyte as well as water homeostasis.
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PMID:A locally generated angiotensin system in rat carotid body. 1213 71

Insulin-like growth factor II (IGF-II) is thought to play an important role in development and growth of vertebrates. In contrast to mammals, the IGF-II gene is expressed at a high level from the early stages of embryonic development until the adult stage and IGF-II peptide is produced in virtually all organs of bony fish, indicating a physiological importance of IGF-II 'under water'. Therefore, we describe here the complete nucleotide sequence (accession no. X97225) and organization of the chum salmon IGF-II gene. In addition, the phylogenetic relationship of the IGF-II hormones is analysed. Although the chum salmon contains two non-allelic insulin and IGF-I genes, only one IGF-II gene could be identified. The chum salmon IGF-II gene consists of four exons and is comprised of 7992 bp from the putative transcription initiation site to the poly(A) site. Activation of the only promoter of the salmon IGF-II gene gives rise to a single 4 kb transcript. The fish IGF-II gene is much smaller and simpler organized than its known mammalian counterparts that are governed by several tissue-specific and developmental stage-dependent promoters. All known mammalian IGF-II genes to date have been found to form a conserved linkage group with the insulin and tyrosine hydroxylase (TH) genes and are organized as TH-insulin-IGF-II genomic locus. However, in our study we could find no linkage between the insulin and IGF-II genes, or between the insulin, TH and IGF-II genes, at least within approximately 20 kb of the chum salmon IGF-II genomic sequence. In spite of minor differences, the overall organization of the IGF-II genes turned out to be very similar in bony fish. A limited analysis of the phylogenetic relationship between IGF-II prohormones indeed showed a very conservative phylogenesis of IGF-II in bony fish that may indicate the particular significance of IGF-II in these animals.
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PMID:Complete nucleotide sequence of the chum salmon insulin-like growth factor II gene. 1235 57

The reaction mechanism for the formation of the hydroxylating intermediate in aromatic amino acid hydroxylases (i.e., phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase) was investigated by means of hybrid density functional theory. These enzymes use molecular oxygen to hydroxylate both the tetrahydrobiopterin cofactor and the aromatic amino acid. A mechanism is proposed in which dioxygen forms a bridging bond between the cofactor and iron. The product is an iron(II)-peroxy-pterin intermediate, and iron was found to be essential for the catalysis of this step. No stable intermediates involving a pterin radical cation and a superoxide ion O(2)(-) were found on the reaction pathway. Heterolysis of the O-O bond in the iron(II)-peroxy-pterin intermediate is promoted by one of the water molecules coordinated to iron and releases hydroxypterin and the high-valent iron oxo species Fe(IV)=O, which can carry out subsequent hydroxylation of aromatic rings. In the proposed mechanism, the formation of the bridging C-O bond is rate-limiting in the formation of Fe(IV)=O.
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PMID:Mechanism of dioxygen cleavage in tetrahydrobiopterin-dependent amino acid hydroxylases. 1250 69

The extracellular regulated kinase (ERK) pathway was studied to determine its role in neuronal plasticity related to the development of nicotine dependence. Levels and phosphorylation state of ERK, cAMP response element binding protein (CREB) and proline-rich/Ca2+-activated tyrosine kinase (PYK2), and levels of tyrosine hydroxylase (TH), were determined using western blotting. C57Bl/6J mice received acute or chronic nicotine (200 microg/mL) in their drinking water or were withdrawn from nicotine for 24 h following chronic exposure. CREB phosphorylation was reduced in the nucleus accumbens following chronic nicotine, consistent with previous reports that decreased accumbens CREB activity increases drug reinforcement. In contrast, CREB phosphorylation was increased in the prefrontal cortex following chronic nicotine exposure and in the ventral tegmental area during nicotine withdrawal. In addition, total and phosphorylated ERK decreased in the amygdala following chronic nicotine exposure, but ERK phosphorylation increased in the prefrontal cortex. TH levels increased in both the amygdala and prefrontal cortex, supporting the hypothesis that increased catecholaminergic tone contributes to nicotine reinforcement. Overall, these results support a role for ERK and CREB activity in neural plasticity associated with nicotine dependence.
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PMID:In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57Bl/6J mice. 1261 43

Both human epidermal melanocytes and keratinocytes have the full capacity for de novo synthesis of 6(R) L-erythro 5,6,7,8, tetrahydrobiopterin, the essential cofactor for the rate limiting step in catecholamine synthesis, via tyrosine hydroxylase. Catecholamine synthesis has been demonstrated in proliferating keratinocytes of the epidermis in human skin. This study presented herein identified for the first time the expression of tyrosine hydroxylase isozyme I mRNA within the melanocyte. The location of the enzyme was demonstrated in both the cytosol and melanosomes of human epidermal melanocytes, using immunohistochemistry and immunofluorescence double staining as well as immunogold electron microscopy. High-performance liquid chromatography (HPLC) analysis of pure melanosomal extracts from the human melanoma cell line, FM94, confirmed the production of L-dopa within these organelles. In addition, enzyme activities for both tyrosine hydroxylase and tyrosinase were measured in the same preparations, by following the catalytic release of tritiated water from L-[3,5-3H]tyrosine. The melanosomal membrane location of tyrosine hydroxylase together with tyrosinase implies a coupled interaction, where L-dopa production facilitates the activation of tyrosinase. Our results support a direct function for tyrosine hydroxylase in the melanosome via a concerted action with tyrosinase to promote pigmentation.
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PMID:Tyrosine hydroxylase isoenzyme I is present in human melanosomes: a possible novel function in pigmentation. 1263 Dec 48

Glucagon-like peptide-1 (GLP-1) released from the gut is an incretin that stimulates insulin secretion. GLP-1 is also a brain neuropeptide that has diverse central actions, including inhibition of food and water intake, gastric emptying, and stimulation of neuroendocrine responses characteristic of visceral illness. Both intravenous and intracerebroventricular administration of GLP-1 receptor (GLP-1R) agonists increase blood pressure and heart rate and induce Fos-like immunoreactivity (Fos-IR) in autonomic regulatory sites in the rat brain. The area postrema (AP) is a circumventricular organ and has been implicated in processing visceral sensory information. GLP-1Rs are densely expressed in the AP, and peripheral GLP-1R agonists induce Fos-IR in AP neurons to a greater degree than intracerebroventricular administration. Because the AP lacks a blood-brain barrier, we hypothesized that the AP is a key site for peripheral GLP-1 to activate central autonomic regulatory sites. In this study, we found that many tyrosine hydroxylase (TH)-containing neurons in the AP expressed GLP-1Rs and Fos-IR after intravenous GLP-1R agonists. Furthermore, intravenous but not intracerebroventricular GLP-1R agonists induced TH transcription in the AP in vivo. In addition, GLP-1R agonists directly activated TH transcription in an in vitro cell system. Finally, we found that GLP-1-responsive TH neurons in the AP innervate autonomic control sites, including the parabrachial nucleus, nucleus of solitary tract, and ventrolateral medulla. These findings suggest that catecholamine neurons in the AP link peripheral GLP-1 and central autonomic control sites that mediate the diverse neuroendocrine and autonomic actions of peripheral GLP-1.
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PMID:Glucagon-like peptide-1-responsive catecholamine neurons in the area postrema link peripheral glucagon-like peptide-1 with central autonomic control sites. 1268 81

There is only limited morphologic information on long-term alterations and neurotransmitter changes after perinatal asphyxia, and no long-term study showing neurodegeneration has been reported so far. We used an animal model for perinatal asphyxia well documented in the rat to investigate the guinea pig as a species highly mature at birth. Cesarean section was performed on full-term pregnant guinea pigs, and pups, still in membranes, were placed into a water bath at 37 degrees C for asphyxia periods from 2 to 4 min. Thereafter pups were given to surrogate mothers and examined at 3 mo of age. We studied brain areas reported to be hypoxia-sensitive. Neurodegeneration was evaluated by fluoro-jade, neuronal loss by Nissl, reactive gliosis by glial fibrillary acidic protein staining, and differentiation by neuroendocrine-specific protein C immunoreactivity. We tested tyrosine hydroxylase, the vesicular monoamine transporter, and dopamine beta-hydroxylase, representing the monoaminergic system; the vesicular acetylcholine transporter; and the excitatory amino acid carrier 1. Neurodegeneration was evident in cerebellum, hippocampal area CA1, and hypothalamus, and neuronal loss could be observed in cerebellum and hypothalamus; gliosis was observed in cerebellum, hippocampus, hypothalamus, and parietal cortex; dedifferentiation was found in hypothalamus and striatum; and monoaminergic, cholinergic, and amino acidergic deficits were shown in several brain regions. The major finding of the present study was that neurodegeneration and dedifferentiation evolved in the guinea pig, a species highly mature at birth. The relevance of this contribution is that a simple animal model of perinatal asphyxia resembling the clinical situation of intrauterine hypoxia-ischemia and presenting with neurodegeneration was characterized.
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PMID:Neurodegeneration, neuronal loss, and neurotransmitter changes in the adult guinea pig with perinatal asphyxia. 1286 99

The effect of perinatal asphyxia on brain development was studied with organotypic cultures from substantia nigra, neostriatum and neocortex. Asphyxia was induced by immersing foetuses-containing uterine horns removed from ready-to-deliver rats into a water bath for 20 min. Following asphyxia, the pups were nursed by a surrogate dam and sacrificed after 3 days to prepare organotypic cultures. Non-asphyxiated caesarean-delivered pups were used as controls. Morphological features were recorded during in vitro development. At day in vitro (DIV) 24, the cultures were treated for histochemistry using fast red for cell nucleus labelling and antibodies against tyrosine hydroxylase for dopaminergic neurons. Compared to controls, cultures from asphyxiated pups revealed a diminished integration quantified during 21 DIV. After immunocytochemistry and camera lucida reconstruction, tyrosine hydroxylase-positive neurons showed a decreased number of neurites from secondary and higher level branching, demonstrating a vulnerability of the dopaminergic systems after perinatal asphyxia.
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PMID:Perinatal asphyxia impairs connectivity and dopamine neurite branching in organotypic triple culture from rat substantia nigra, neostriatum and neocortex. 1293 22


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