Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:1.14.16.2 (tyrosine hydroxylase)
14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypothalamic magnocellular neurons constitute a good model of neurochemical plasticity, because a single neuron can express various combinations of neuropeptides and enzymes under different physiological conditions. Tyrosine hydroxylase has been shown to occur ectopically in various non-catecholaminergic neurons. We investigated the expression of tyrosine hydroxylase and its possible role in the magnocellular neurons of the supraoptic and paraventricular nuclei in salt-loaded and lactating rats, using in situ hybridization and immunohistochemistry, alone or combined, in light and electron microscopy. Our results demonstrated that almost 25% of the magnocellular neurons in the supraoptic nucleus and 15% in the paraventricular nucleus expressed tyrosine hydroxylase in salt-loaded rats, and 10% in the supraoptic nucleus of two-day lactating rats. Double labelling showed that this tyrosine hydroxylase was essentially synthesized in magnocellular neurons expressing vasopressin. The ultrastructural localization of tyrosine hydroxylase was less homogeneous in the cytoplasm of magnocellular neurons than in periventricular neurons. In lactating and salt-loaded rats, magnocellular neurons were devoid of the catecholamine biosynthesis markers aromatic L-amino acid decarboxylase, L-3,4 dihydroxyphenylalanine, dopamine and GTP-cyclohydrolase I. Tyrosine hydroxylase expression did not increase after rats were injected with reserpine. Our results indicate that the phenotype of the magnocellular neurons expressing tyrosine hydroxylase in lactating and salt-loaded rats is non-catecholaminergic, and suggest that this tyrosine hydroxylase might be involved in osmoregulation.
...
PMID:Ectopic expression of non-catecholaminergic tyrosine hydroxylase in rat hypothalamic magnocellular neurons. 1061 5

The effect of dopamine (DA) was investigated on acutely dissociated rat substantia nigra pars compacta (SNc) neurones by using patch clamp recording. The SNc neurones could be classified into two groups. About 75% of large neurones (>30 microm in diameter) were tyrosine hydroxylase (TH) positive while almost all small neurones (<20 microm) were TH negative. In the large neurones, DA hyperpolarized the membrane, resulting in a reduction of the frequency of spontaneous action potentials in current-clamp mode and induced an inward rectifier K+ current in voltage-clamp mode. Quinpirole, a D2 receptor agonist, mimicked the DA action. S(-)-sulpiride, a D2 receptor antagonist, inhibited the DA-induced current (I(DA)) more effectively than SKF83566, a D1 receptor antagonist. Intracellular application of either guanosine 5'-O-(2-thiodiphosphate) (GDP-betaS) or pertussis toxin (IAP) suppressed I(DA). Guanosine 5'-O-(3-thiotriphosphate) (GTP-gammaS) sustained the DA response. Modulators for cAMP such as forskolin and isobutylmethylxathine, H-89, a protein kinase A inhibitor, and chelerythrine, a protein kinase C inhibitor, had no effect on I(DA). The frequency of DA-induced single channel currents in the inside-out patch configuration, for which the unitary conductance was 56.6pS, was greatly reduced by the replacement of GTP with GDP perfused at the cytosolic side. These results suggest that DA acts on a D2-like receptor and activates directly an IAP-sensitive G protein coupled with inward rectifier K+ channels, resulting in a decrease in the spontaneous firing activities of rat SNc dopaminergic neurones.
...
PMID:Dopamine activates inward rectifier K+ channel in acutely dissociated rat substantia nigra neurones. 1067 Apr 14

The incubation of cultured fetal mesencephalic neurons with Delta(9)-tetrahydrocannabinol (Delta(9)-THC) increased the activity of tyrosine hydroxylase (TH) and this increase was reversed by SR141716A, a specific antagonist for cannabinoid CB(1) receptors. In the present work, we extended these earlier observations by addressing two objectives. First, we characterized at a molecular level the presence of CB(1) receptors in cultured fetal mesencephalic neurons using two strategies: (i) analyzing the presence of CB(1) receptor gene transcripts by Northern blot, and (ii) measuring [3H]WIN-55,212-2 binding in membrane fractions obtained from these cells, as well as evaluating the potential increase in [35S]-guanylyl-5'-O-(gamma-thio)-triphosphate ([35S]GTPgammaS) binding caused by the activation of these receptors with WIN-55,212-2, a synthetic agonist. Northern blot analyses demonstrated the presence of small, but measurable levels of CB(1) receptor mRNA in cultured fetal mesencephalic neurons. The presence of these transcripts was accompanied by the presence of receptor binding protein, as revealed by a small, but specific, [3H]WIN-55, 212-2 binding in membrane fractions obtained from these cells. These CB(1) receptors are coupled to GTP-binding proteins, as the incubation of membrane fractions obtained from these cells with WIN-55,212-2 slightly, but significantly increased [35S]GTPgammaS binding. This fact indicated the existence, not only of receptor binding, but also of a functional receptor transduction pathway. As a second objective, we examined the potential colocalization of CB(1) receptors and TH in these cells by double-labelling immunocytochemistry. We also determined by Western blotting whether the previously observed Delta(9)-THC-induced increase in TH activity was accompanied by increased TH protein levels. Cultured fetal mesencephalic neurons exhibit diverse cell phenotypes, with CB(1) receptors localized only on TH-containing neurons. In addition, we found that the incubation of fetal mesencephalic neurons with medium containing Delta(9)-THC increased TH protein levels, in concordance with the previously reported increase in TH activity. Collectively, our results support the notion that CB(1) receptors are present in cultured fetal mesencephalic TH-containing neurons, despite their absence in the corresponding neurons in the adult brain. Thus, it is likely that the effects of cannabinoids on TH activity are direct. All this data strengthen the view that cannabinoid receptors are atypically located during brain development and that they might play an important role during this process, in particular on the phenotypical expression of TH-containing neurons.
...
PMID:Cannabinoid CB(1) receptors colocalize with tyrosine hydroxylase in cultured fetal mesencephalic neurons and their activation increases the levels of this enzyme. 1070 May 52

The dystonias are a common clinically and genetically heterogeneous group of movement disorders. More than ten loci for inherited forms of dystonia have been mapped, but only three mutated genes have been identified so far. These are DYT1, encoding torsin A and mutant in the early-onset generalized form, GCH1 (formerly known as DYT5), encoding GTP-cyclohydrolase I and mutant in dominant dopa-responsive dystonia, and TH, encoding tyrosine hydroxylase and mutant in the recessive form of the disease. Myoclonus-dystonia syndrome (MDS; DYT11) is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles. Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease. In addition, patients often show prominent psychiatric abnormalities, including panic attacks and obsessive-compulsive behavior. In most MDS families, the disease is linked to a locus on chromosome 7q21 (refs. 11-13). Using a positional cloning approach, we have identified five different heterozygous loss-of-function mutations in the gene for epsilon-sarcoglycan (SGCE), which we mapped to a refined critical region of about 3.2 Mb. SGCE is expressed in all brain regions examined. Pedigree analysis shows a marked difference in penetrance depending on the parental origin of the disease allele. This is indicative of a maternal imprinting mechanism, which has been demonstrated in the mouse epsilon-sarcoglycan gene.
...
PMID:Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome. 1152 94

Intrastriatal delivery of the tyrosine hydroxylase gene by viral vectors is being explored as a tool for local delivery of L-dopa in animals with lesions of the nigrostriatal pathway. The functional effects reported using this approach have been disappointing, probably because the striatal L-dopa levels attained have been too low. In the present study, we have defined a critical threshold level of L-dopa, 1.5 pmol/mg of tissue, that has to be reached to induce any significant functional effects. Using new generation high-titer recombinant adeno-associated virus vectors, we show that levels of striatal L-dopa production exceeding this threshold can be obtained provided that tyrosine hydroxylase is coexpressed with the cofactor synthetic enzyme, GTP-cyclohydrolase-1. After striatal transduction with this combination of vectors, substantial functional improvement in both drug-induced and spontaneous behavior was observed in rats with either complete or partial 6-hydroxydopamine lesions of the nigrostriatal pathway. However, complete reversal of motor deficits occurred only in animals in which part of the striatal dopamine innervation was left intact. Spared nigrostriatal fibers thus may convert L-dopa to dopamine and store and release dopamine in a more physiologically relevant manner in the denervated striatum to mediate better striatal output-dependent motor function. We conclude that intrastriatal L-dopa delivery may be a viable strategy for treatment and control of adverse side effects associated with oral L-dopa therapy such as on-off fluctuations and drug-induced dyskinesias in patients with Parkinson's disease.
...
PMID:Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer. 1191 5

Previously, (-)-trans-1-phenyl-3-N,N-dimethylamino-1,2,3,4-tetrahydronaphthalene ([-]-trans-H(2)-PAT) was shown to activate stereospecifically histamine H(1) receptors coupled to modulation of tyrosine hydroxylase activity in guinea pig and rat forebrain in vitro and in vivo. Furthermore, the novel radioligand [(3)H](-)-trans-H(2)-PAT was shown to label selectively H(1) receptors in guinea pig and rat brain with high affinity (K(D), ~0.1 and 0.5 nM, respectively) and a B(max) about 50 and 15%, respectively, of that observed for the H(1) antagonist radioligand [(3)H]mepyramine. In the current study, [(3)H](-)-trans-H(2)-PAT-labeled cloned guinea pig and human H(1) receptors in Chinese hamster ovary (CHO) cell membranes with high affinity (K(D), ~0.08 and 0.23 nM, respectively) and a B(max) about 15% of that observed for [(3)H]mepyramine. The binding of H(2)-PAT to H(1) receptors in both CHO-H(1) cell lines was stereoselective with the (-)-trans-isomer having affinity (K(i), ~1.5 nM) about 4-, 20-, and 50-times higher than the (-)-cis-, (+)-trans-, and (+)-cis-isomers, respectively; the affinity of (-)-trans-H(2)-PAT was unaffected by excess GTP. In functional assays, (-)-trans-H(2)-PAT was a full antagonist of histamine H(1)-mediated stimulation of phospholipase C (PLC) and [(3)H]inositol phosphates (IP) formation in CHO-H(1) cells, a full inverse agonist of constitutively active H(1) receptors in COS-7-H(1) cells, and a full competitive antagonist (pA(2) = 9.2) of histamine H(1)-mediated contraction of guinea pig ileum. It is concluded that (-)-trans-H(2)-PAT is an antagonist at H(1) receptors coupled to PLC/IP formation and smooth muscle contraction. Meanwhile, the observation that [(3)H](-)-trans-H(2)-PAT labels only a subpopulation of H(1) receptors and that (-)-trans-H(2)-PAT activates H(1) receptors coupled to modulation of tyrosine hydroxylase suggests that there may be post-translational H(1) receptor heterogeneity.
...
PMID:A novel phenylaminotetralin radioligand reveals a subpopulation of histamine H(1) receptors. 1206 34

Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurones against toxic and physical damage. In addition, GDNF promotes differentiation and structural integrity of dopaminergic neurones. Here we show that GDNF can support the function of primary dopaminergic neurones by triggering activation of GTP-cyclohydrolase I (GTPCH I), a key enzyme in catecholamine biosynthesis. GDNF stimulation of primary dopaminergic neurones expressing both tyrosine 3-monooxygenase and GTPCH I resulted in a dose-dependent doubling of GTPCH I activity, and a concomitant increase in tetrahydrobiopterin levels whereas tyrosine 3-monooxygenase activity was not altered. Actinomycin D, asan inhibitor of de novo biosynthesis, abolished any GDNF-mediated up-regulation of GTPCH I activity. However, GTPCH I mRNA levels in primary dopaminergic neurones were not altered by GDNF treatment, suggesting that the mode of action for that up-regulation is not directly connected to the regulation of GTPCH I transcription. We conclude that GDNF, in addition to its action in structural differentiation, also promotes differentiation regarding expression and enzymatic activity of a crucial component in the dopaminergic biosynthetic pathway.
...
PMID:Glial cell line-derived neurotrophic factor up-regulates GTP-cyclohydrolase I activity and tetrahydrobiopterin levels in primary dopaminergic neurones. 1235 77

Previously we reported that the synthesis of catecholamines, dopamine, and noradrenaline was enhanced by overexpression of V-1 protein, a neuronal protein active in the initial stage of development of the rat cerebellum, in the neuronal cell line PC12D, a model of dopamine cells (Yamakuni et al. [1998] J. Biol. Chem. 273:27051-27054). To investigate the physiological role of this protein, we examined the effect of V-1 overexpression on cell toxicity induced by nitric oxide (NO) used at low concentrations. Two clones of PC12D cells overexpressing V-1, transfectants termed V1-46 and V1-69, were significantly more resistant to NOR3 (an NO donor) but not to etoposide (an inhibitor of topoisomerase II)-induced apoptotic cell death than the control cells (termed C-7 and C-9) that had been transfected with the vector alone. The addition of L-DOPA, dopamine, or noradrenaline to the medium did not abolish NOR3-induced cell death in PC12D cells. Moreover, pretreatment of V1-46 and V1-69 cells with L-alpha-methyl-p-tyrosine (alpha-MPT), an inhibitor of tyrosine hydroxylase, to inhibit catecholamine biosynthesis did not affect the resistance to NO toxicity. These results indicate that the catecholamine levels increased by V-1 overexpression did not produce the protection against NOR3-induced toxicity. We further showed that overexpression of V-1 enhanced the synthesis of (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)). In addition, pretreatment with BH(4) or with sepiapterin, which is converted to BH(4) intracellularly, significantly protected PC12D cells in a dose-dependent manner. The increased BH(4) synthesis by V-1 overexpression was dose dependently inhibited by pretreatment with diaminohydroxypyrimidine (DAHP), an inhibitor of GTP-cyclohydrolase I, which is the rate-limiting enzyme for the biosynthesis of BH(4), concomitantly with the loss of protective effect afforded by V-1 overexpression. Furthermore, the addition of BH(4) or sepiapterin to DAHP-pretreated V146 and V1-69 cells restored cell viability. Taken together, these results indicate that V1 protein plays an important role in protection against cell death induced by NO at low levels by promoting the synthesis of BH(4). Moreover, these findings suggest the up-regulation of V1 expression as a possible therapeutic target for protection against the insult of NO-induced oxidative stress.
...
PMID:Overexpression of V-1 prevents nitric oxide-induced cell death: involvement of enhanced tetrahydrobiopterin biosynthesis. 1277 12

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) is an enzyme that catalyses the conversion of hypoxanthine and guanine into their respective nucleotides. Inherited deficiency of the enzyme is associated with a loss of striatal dopamine in both mouse and man. Although HPRT is not directly involved in the metabolism of dopamine, it contributes to the supply of GTP, which is used in the first and rate-limiting step in the synthesis of tetrahydrobiopterin (BH4). Since BH4 is required as a cofactor for tyrosine hydroxylase in the synthesis of dopamine, any limitation in the supply of GTP could interfere with the synthesis of dopamine. The current studies were designed to address the hypothesis that the reduced striatal dopamine in mice with HPRT deficiency results from reduced availability of BH4. The mutant mice had small reductions in striatal BH4, with normal BH4 levels in other brain regions. Liver BH4 was normal in HPRT-deficient mutant mice, and a phenylalanine challenge test failed to reveal any evidence for impaired hepatic phenylalanine hydroxylase, another BH4-dependent enzyme. Although striatal BH4 content is not normal, supplementation with BH4 or L-dopa failed to correct the striatal dopamine deficiency of the mutant mice, suggesting that BH4 limitation is not responsible for the dopamine loss.
...
PMID:Tetrahydrobiopterin deficiency and dopamine loss in a genetic mouse model of Lesch-Nyhan disease. 1515 47

Parkinson's disease (PD) is a good target for gene therapy because the lesion is localized to the substantia nigra (SN). There are several approaches in gene therapy for PD. For enhancing dopamine production, the candidate genes are tyrosine hydroxylase, AADC and/or GTP cyclohydroxylase I. The second approach is a neuroprotective strategy, which is based on the usage of genes for neurotophic factors or anti-apoptotic agents. We also showed that Apaf-1-dominant negative inhibitor delivery using an AAV vector system could prevent nigrostriatal degeneration in MPTP mice, suggesting that it might be an anti-mitochondrial apoptotic gene therapy for PD. In 2003, the first gene therapy trial for PD performed at New York Weill Cornell Medical Center. The treatment is designed to deliver glutamic acid decarboxylase (GAD), the gene responsible for making GABA, into the subthalamic nucleus to "quiet down" that nucleus and alleviate Parkinson's symptoms. The last approach is replacement of disease for autosomal recessive PD. Because autosomal recessive juvenile parkinsonism (ARJP) involves the loss of function of parkin gene, gene therapy employing the parkin gene may prevent nigral cell death.
...
PMID:[Future of gene therapy for Parkinson's disease]. 1565 40


<< Previous 1 2 3 4 5 Next >>

---