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)

Possible neurotoxic actions of intracerebral injections of ibotenic acid, a conformationally restricted analogue of glutamic acid, have been evaluated in rat brain and compared with those of kainic acid. Light microscopical analysis revealed that ibotenic acid produced a marked disappearance of nerve cells in all areas studied, namely striatum, the hippocampal formation, substantia nigra and piriform cortex. Lesions in areas distant to the injection site were not seen. Axons of passage and nerve terminals of extrinsic origin did not seem to be damaged, since, e.g., no apparent degeneration of the dopaminergic terminals in the neostriatum was observed except for a small area surrounding the cannula. In the neostriatum, enkephalin immunoreactive neuronal cell bodies as well as nerve terminals disappeared after injection of ibotenic acid into this nucleus. After injection into the substantia nigra tyrosine hydroxylase immunoreactive cell bodies in the zona compacta disappeared, whereas no certain effect could be seen on the enkephalin immunoreactive nerve fibers. In vitro experiments, conducted with striatal synaptosomal and membrane preparations, showed that ibotenic acid differed from kainic acid by being devoid of a significant inhibitory effect on high affinity glutamate uptake and by having a low affinity for 3H-kainic acid binding sites. Furthermore, ibotenic acid did not interfere with the binding of a number of radioligands for other transmitter receptors. As compared to kainic acid, ibotenic acid has the advantage of being less toxic to the animals and of producing more discrete lesions, possibly due to faster metabolism and/or other fundamental biochemical differences. Because of these special features, ibotenic acid seems to represent a valuable new tool in the morphological and functional analysis of central neuronal systems.
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PMID:Ibotenic acid-induced neuronal degeneration: a morphological and neurochemical study. 4 Aug 8

We have examined the expression of mRNAs encoding five major neurotransmitter-synthesizing enzymes in MAH cells, a clonal cell line derived by retroviral immortalization of a rat embryonic sympathoadrenal progenitor cell. These mRNAs include tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), tryptophan hydroxylase (TpH), and glutamic acid decarboxylases (GADs) 1 and 2. We find that MAH cells express high levels of TH mRNA and low levels of ChAT and TpH mRNAs. Neither GAD1 nor GAD2 mRNAs are detectable using an RNase protection assay with a detection limit of less than one transcript per cell. A similar pattern of mRNA expression is observed in postnatal superior cervical ganglia, adrenal medulla, and in PC12 cells. Transmitter synthesis and accumulation assays indicate that MAH cells can synthesize both catecholamines and acetylcholine. Thus the TH and ChAT mRNAs detected in these cells are likely to be translated into active enzyme. To corroborate these data obtained using MAH cells, we performed similar transmitter synthesis and accumulation assays on sympathoadrenal progenitors directly isolated from E14.5 fetal adrenal glands by fluorescence-activated cell sorting. These progenitor cells also synthesize and accumulate both catecholamines and acetylcholine, albeit to different extents than MAH cells. Both MAH cells and their nonimmortal counterparts are able to increase slightly their cholinergic function upon short-term exposure to CDF/LIF, a factor known to induce acetylcholine synthesis in postmitotic sympathetic neurons. Taken together, these data suggest that progenitor cells in the sympathoadrenal lineage acquire the ability to simultaneously transcribe several different neurotransmitter enzyme genes early in development, prior to their choice of final cell fate. At the same time, the progenitors possess receptors which regulate expression of these genes in response to environmental factors. This ability may permit the cells to choose from several different transmitter phenotypes in response to different environments, as they migrate through the embryo. The persistent transcription of these genes in adult cells, moreover, may in part account for the phenotypic plasticity of cells in this lineage.
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PMID:Co-expression of multiple neurotransmitter enzyme genes in normal and immortalized sympathoadrenal progenitor cells. 168 90

We measured biochemical markers of excitability in brain excised for neurosurgical therapy of epilepsy. Intraoperative electrocorticography was used to identify and compare samples from regions of persistent interictal spike discharges and areas of the cerebral convexity which were free of interictal spiking. We found that interictal spiking was associated with elevated tissue levels of the excitatory amino acids glutamic acid (26%, p less than 0.001) and aspartic acid (25%, p less than 0.05). There was also a significant increase in the activity of the enzymes glutamic acid dehydrogenase (20%, p less than 0.01) and aspartate acid aminotransferase (18%, p less than 0.01) which are involved in their formation. There was no change in the levels of the inhibitory neurotransmitters GABA or taurine. We also found a significant increase in the activity of tyrosine hydroxylase (52%, p less than 0.001), the rate controlling enzyme in catecholamine biosynthesis. There was a reduction in the density (Bmax) of cortical alpha-1 adrenoceptors (26%, p less than 0.01) and a concomitant diminution of receptor coupled phosphatidylinositide metabolism (21%, p less than 0.01). This blunting of inhibitory noradrenergic transmembrane signaling may contribute to a relative imbalance between excitatory and inhibitory mechanisms in epileptogenic neocortex.
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PMID:Biochemical markers of excitability in human neocortex. 177 85

[3H]-Flunitrazepam (FNT) binding was measured in the post-mortem brains of 13 chronic schizophrenics and 10 controls whose mean ages and death-to-freezing intervals were the same in each group. The specific binding of [3H]-FNT to the medial frontal cortex, orbitofrontal cortex, orbital cortex, medial and inferior temporal gyri, superior temporal gyrus, cornu Ammonis 1-3 and putamen was significantly higher in schizophrenics than in controls. Specific binding to the eye movement area (frontal eye field), motor cortex, lateral occipitotemporal gyrus, dentate gyrus of the hippocampus and secondary and tertiary visual cortex did not differ in the two groups. Type 1 benzodiazepine (BZ) binding sites in the superior temporal gyrus of schizophrenics, determined from the displacement of [3H]-FNT binding using a triazolopyridazine, CL 218,872 (200 nM), were significantly higher than in the control group. The increase in type 2 BZ binding sites was not significant. Antipsychotic or benzodiazepine medication did not appear to affect the results. There were significant correlations between specific [3H]-FNT binding and concentration of GABA (positive) and of glutamic acid (negative), specific [3H]-kainic acid binding (positive), activity of tyrosine hydroxylase (positive), and substance P-like immunoreactivity (positive) in many areas of the brain. The Bmax of [3H]-spiperone binding in the putamen was also correlated positively with specific [3H]-FNT binding. These data suggest that dysfunction of BZ receptors may be involved in the pathogenesis and some symptoms of chronic schizophrenia.
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PMID:Benzodiazepine receptors increase in post-mortem brain of chronic schizophrenics. 255 17

Studies of various parameters of amino acid and catecholamine metabolism in human cerebral cortex have provided a number of biochemical markers that appear to delineate areas of focal epileptic activity. These observations have been consolidated further by investigations of a number of experimental models of epilepsy in animals. In appraising this data, it is important to take into consideration whether the tissue samples were obtained during an actual seizure state or in an interictal period. It is also important when possible to assess the extent of astrogliosis and neuronal loss. Sites of spontaneously active epileptic spiking in the cerebral neocortex have a somewhat different amino acid profile when compared to gray matter obtained from surrounding nonspiking gyri several centimeters away. There is an elevation in glycine content, a relative diminution in taurine, and a trend towards lowered glutamic acid levels. However, the concentrations of the eight amino acids measured appear in both the foci and surround to still be within the general range for normal tissue. Measurements of key enzymes involved in the synthesis and regulation of neurotransmitters provide a complementary method of evaluating functional changes in epileptic brain as they are generally less labile than their substrates. There is a moderate increase in the activity of glutamic acid dehydrogenase, an enzyme that plays an important role in the synthesis of glutamic acid from glucose. In some patients a decrease in glutamic acid decarboxylase has also been reported: this enzyme forms gamma-aminobutyric acid (GABA) from glutamic acid and is thus important for inhibition in the central nervous system. Moreover, there is a striking increase in the activity of tyrosine hydroxylase, the rate-limiting enzyme responsible for catecholamine synthesis. The possibility of a focal abnormality in catecholamine metabolism is reinforced by the simultaneous finding of a relative decrease in the number of alpha-1 postsynaptic receptor sites. An important marker of energy metabolism in neural tissue, Na+,K+-ATPase activity, has also been found to be decreased in actively spiking human cerebral cortex. Data from experimental animal foci produced by topical application of convulsant agents show a consistent drop in glutamic acid tissue content. This can be matched to an efflux of glutamic acid from the cortical surface, which in turn is proportional to the electrographic activity of the spike focus. In addition, there is often also a decrease in taurine and GABA in such foci, as well as an increase in the levels of a number of neutral amino acids.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Amino acid and catecholamine markers of metabolic abnormalities in human focal epilepsy. 287 18

A low-molecular-weight component present in medium conditioned by cultured chick liver cells (LCM) enhances the adrenergic properties of dissociated chick superior cervical ganglion (SCG) neurons in culture (Zurn and Mudry, 1986). This substance cannot replace NGF as a survival, growth, or differentiation factor. However, in the presence of NGF, it stimulates neuronal metabolism and catecholamine (CA), but not ACh production by the SCG neurons. The effect on transmitter production is greater than that on neuronal metabolism. Yet this is not due to an increase in the specific activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in CA synthesis. Interestingly, the effect of LCM on CA and ACh production, but not on neuronal metabolism, is potentiated in the presence of a large excess of NGF. The active component(s) present in LCM has a molecular weight lower than 500 Da and is not inactivated by heat or pronase treatment. So far, none of the small molecules tested (ascorbic acid, pyruvate, glucose, L-glutamic acid, glutathione, etc.) were able to mimic the effects of LCM on the SCG neurons. Thus this report describes a novel low-molecular-weight component different from NGF that promotes metabolism and adrenergic development in cultured chick sympathetic neurons.
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PMID:A new low-molecular-weight component promoting adrenergic development in cultured chick sympathetic neurons. 289 Jul 20

In the analysis of post-mortem brains of 14 chronic schizophrenic patients and 10 controls, biochemical evidence of a hyperdopaminergic state was found in the basal ganglia of schizophrenics; tyrosine hydroxylase activity was increased with a concomitant increase of homovanillic acid. Unusually high tyrosine hydroxylase activity was noted in 2 schizophrenic cases. The Bmax value of 3H-spiperone binding for schizophrenics was higher than the controls. We also found increased specific binding of 3H-kainic acid to the prefrontal cortex in schizophrenics. A negative correlation existed between 3H-kainic acid binding in the medial frontal cortex, and glutamic acid content in various brain areas. Increased immunoreactivity of substance P was found in more than ten brain areas. Methionine-enkephalin was also increased in three areas of the prefrontal cortex of schizophrenics. These results suggest that the hyperdopaminergic state co-existed with glutamatergic hypofunction and increased neuropeptides in various brain areas of chronic schizophrenic patients.
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PMID:Neurotransmitters, receptors and neuropeptides in post-mortem brains of chronic schizophrenic patients. 290 13

Five enzymes involved in glutamic acid, GABA, and catecholamine metabolism were measured in epileptic human brain. Electrocorticographically defined areas of focal spiking were compared with samples from surrounding nonspiking cortex. Comparative enzyme activities were as follows (mumol/h/g wet wt): glutamic acid dehydrogenase (GDH)--spiking 135.77 +/- 10.22 (mean +/- SEM), nonspiking 118.58 +/- 9.42 (p less than 0.001, N = 17); glutamic acid decarboxylase--spiking 10.63 +/- 0.95, nonspiking 9.96 +/- 1.10 (NS, N = 13); GABA-aminotransferase--spiking 36.49 +/- 1.05, nonspiking 36.46 +/- 1.48 (NS, N = 12); glutamine synthetase--spiking 96.94 +/- 3.81, nonspiking 96.52 +/- 4.10 (NS, N = 20); and tyrosine hydroxylase (TH; nmol/h/g)--spiking 16.23 +/- 2.39, nonspiking 10.67 +/- 1.95 (p less than 0.001, N = 14). Increased activity of GDH and TH may prove useful to characterize further areas of active spiking in human focal epilepsy.
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PMID:Enzyme changes in actively spiking areas of human epileptic cerebral cortex. 614 16

A cardiovascular-active pressor area of medullary reticular formation was defined by mapping changes in arterial blood pressure produced by microinjections of the neuroexcitatory amino acid, L-Glutamate (L-Glu). Sites where L-Glu provoked pressor responses larger than 10 mmHg were localized to a rostral longitudinal cell column of the nucleus reticularis rostroventrolateralis (n.RVL) extending 450 microns posteriorly to the facial nucleus. Spinal projections from the ventrolateral medulla were studied with a dual retrograde transport-immunocytochemical method. A striking correspondence was observed between the ventrolateral pressor area (VLPA) of n.RVL and rostrocaudal distribution of a circumscribed population of thoracic reticulospinal neurons containing tyrosine hydroxylase (TH)- or phenylethanolamine N-methyltransferase (PNMT)_immunoreactivity. Quantitative analysis revealed that 72% of the total number of retrogradely labeled neurons within the active area were immunocytochemically positive for TH; 28% of the reticulospinal projection cells were immunonegative. Deposits of L-Glu and dye through the same micropipettes verified a consistent correlation of vasopressor sites and the rostral subset of catecholaminergic neurons. Since comparable numbers of cell bodies in the VLPA contain TH and PNMT all are presumed to be adrenergic. At levels of n.RVL immediately adjacent to the VLPA commencing at a level 450 microns caudal to the facial nucleus, sites were unresponsive to Glu-stimulation or vasodepressor. At these levels, only non-adrenergic reticulospinal neurons project to cervical or thoracic spinal segments. We conclude that the VLPA is highly restricted to a narrow column of n.RVL < 0.5 mm in length and corresponds precisely with a population of predominantly adrenergic thoracic reticulospinal neurons that project exclusively to sympathoadrenal preganglionic motoneurons [cf 46]. These findings corroborate the idea that an adrenergic-spinal pathway may play a role in controlling sympathetic outflow.
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PMID:Adrenergic and non-adrenergic spinal projections of a cardiovascular-active pressor area of medulla oblongata: quantitative topographic analysis. 753 95

Rat tyrosine hydroxylase was expressed in Escherichia coli. High-level expression was obtained after incubation at 27 degrees C for 18 h. The smallest fragment of tyrosine hydroxylase that gave a soluble active molecule was from Leu188 to Phe456. This fragment corresponds directly to the section of phenylalanine hydroxylase that had previously been shown to be this enzyme's catalytic core region. It has been shown that Glu288 plays a critical role in pterin function in phenylalanine hydroxylase. The corresponding residue in tyrosine hydroxylase (Glu332) has no significant role in pterin function. Substitution of a leucine for a proline at position 327 in tyrosine hydroxylase produces a molecule with a K(m) for tetrahydrobiopterin 20-fold higher than that of the wild-type molecule, whereas the same substitution at the corresponding residue in phenylalanine hydroxylase (pro281) has no effect on the kinetic constant for the cofactor. This suggests that corresponding residues in phenylalanine hydroxylase and tyrosine hydroxylase can have different roles in pterin function. Substitution of a leucine for a proline at position 281 in phenylalanine hydroxylase increases the K(m) for phenylalanine > 20-fold over that of the wild-type. Substitution of leucine or alanine for Pro327 or a glutamic acid for Gln313 in tyrosine hydroxylase eliminates the substrate inhibition shown by wild-type tyrosine hydroxylase.
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PMID:Identification of Gln313 and Pro327 as residues critical for substrate inhibition in tyrosine hydroxylase. 876 48


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