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

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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)

DOPA decarboxylase (DDC; aromatic-l-amino acid decarboxylase; EC 4.1.1.28) is absent in retinas from 6-day-old chicken embryos (E6) but is expressed in retina of E8 embryos, in the presumptive outer plexiform layer. Thereafter, DDC appears in cell bodies of presumptive amacrine cells. The dopamine (DA) content of E9/10 and E15/16 retinas, pre-incubated with l-DOPA for 1 h, increased 250- and 600-fold, respectively, showing that DDC is active since early in development. Intercellular communication, measured by endogenous cyclic AMP accumulation, was observed when retinas from E9/10 to E15/16 were pre-incubated for 1 h with 1 mm l-DOPA, washed and followed by incubation in the presence of 0.5 mm 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor. Cyclic AMP accumulation was prevented when pre-incubation with l-DOPA was carried out in the presence of carbidopa. Moreover, the accumulation of cyclic AMP was inhibited by SCH 23390 (2 micro m). The incubation of retinas in medium previously conditioned by retina-pigmented epithelium (RPE) also increased its cyclic AMP content with the characteristics described for l-DOPA. Our results show that dopaminergic communication takes place in the embryonic retina, before tyrosine hydroxylase expression, provided l-DOPA is supplied to the tissue. It also shows that RPE is a potential source of l-DOPA early in development.
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PMID:L-DOPA supply to the neuro retina activates dopaminergic communication at the early stages of embryonic development. 1280 23

The aim of our study was to investigate the expression and the activity of soluble guanylyl cyclase (GC) and phosphodiesterase (PDE) activities that regulate cGMP level in the striatum, hippocampus, and brain cortex in an animal model of PD, induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We observed the increase of total activity and protein level of GC in striatum after MPTP injection. It was accompanied by an enhancement of both mRNA expression and protein level of GCbeta1 subunit. MPTP induces mRNA expression and elevates protein concentration of GCbeta1 in striatum up to 14 days after its injection, which in turn causes a marked enhancement of cGMP formation. Furthermore, the activation of GC occurs through change of maximal enzyme activity (V(max)). Simultaneously, no change in PDE activity has been detected in all investigated regions of the brain after MPTP. MPTP injection caused the elevation of GCbeta1 protein level in both the membrane and cytosol fractions being significantly higher in cytosol. Western blot analysis demonstrated about 45-67% decrease of tyrosine hydroxylase protein content in striatum. These data suggest that NO/cGMP signaling pathway may at least partially contribute to dopaminergic fiber degeneration in the striatum, the damage attributed to PD.
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PMID:Upregulation of guanylyl cyclase expression and activity in striatum of MPTP-induced parkinsonism in mice. 1546 91

A large portion of the central catecholaminergic nerve terminals of the rat are destroyed by administering 6-hydroxydopamine (6-HDA) via the cerebrospinal fluid. Animals lesioned in this way often appear normal, yet show many subtle behavioural abnormalities. We have been examining one example of this phenomenon, the failure of 6-HDA-lesioned rats to increase food intake when given a systemic injection of 2-deoxy-D-glucose (2-DG) (refs 5, 6). This glucose analogue seems to elicit feeding in intact rats due to its inhibition of glycolysis in cerebral chemoreceptor cells. We have proposed that lesioned animals do not eat because of an insufficient central catecholaminergic response to the severe decrease in glucose utilisation induced by 2-DG (ref. 10). If so, then pretreatments which serve to augment this neurochemical response might be expected to reinstate behavioural function. Consistent with this hypothesis, very large increases in telencephalic tyrosine hydroxylase activity in 6-HDA-lesioned animals, which occur following chronic insulin treatment, are associated with the restoration of 2-DG-induced feeding. Many of the physiological effects of catecholamines in the sympathetic nervous system seem to be mediated by an increase in the cyclic AMP concentration of the target cells. Methylxanthenes, such as caffeine and theophylline, inhibit phosphodiesterase, prevent cyclic AMP degradation, and thereby potentiate the catecholamine-stimulated rise in cyclic nucleotide. They also enhance many of the behavioural and physiological effects of catecholamines, presumably by the same mechanism. We therefore sought to determine whether the acute administration of those sympathomimetic agents, in intact and 6-HDA-lesioned rats, also would potentiate 2-DG-induced feeding, a behaviour that seems to be mediated, in part, by central catecholaminergic neurons. We report that caffeine restores the 2-DG-induced feeding response.
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PMID:Caffeine restores feeding response to 2-deoxy-D-glucose in 6-hydroxydopamine-treated rats. 1607 37

In the chick retina, dopaminergic cells are generated between embryonic days 3 and 7 (E3/E7). However, the expression of tyrosine hydroxylase (TH), the first enzyme in the catecholamine synthetic pathway, is only detected after E11/E12. During the interval comprising E7 to E12, signals conveyed by cAMP are important to determine the TH phenotype. The present study shows that pituitary adenylyl cyclase-activating polypeptide (PACAP), via cAMP, is a major endogenous component in defining the TH phenotype of retina dopaminergic cells during development. PACAP type 1 receptor and its mRNA were detected in retinas since E6. PACAP was also immunodetected in cells localized in the inner nuclear layer of retinas since E8. This peptide promoted greater than 10-fold increase in cAMP accumulation of retinas obtained from embryos since E8, an effect that was blocked by PACAP6-38 (PAC1 receptor antagonist). In cultured retina cells from E8 and E9, maintained for 6 days in vitro with 10 nM PACAP (for 5 days), the number of dopaminergic cells expressing tyrosine hydroxylase increased 2.4-fold. The cAMP analog, 8-Br-cAMP and 3-isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor) also increased the number of tyrosine hydroxylase-positive cells by 4- to 6-fold. IBMX plus PACAP treatment resulted in 17-fold increase in the number of cells positive for tyrosine hydroxylase. Under this condition the amount of tyrosine hydroxylase expression, as detected by western blot analysis, was also increased. The protein kinase-A inhibitor, rp-cAMPS, significantly reduced the effect of PACAP. Our data show that this peptide is an important factor influencing the definition of the tyrosine hydroxylase phenotype of retina dopaminergic cells within a narrow window of development.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP) can act as determinant of the tyrosine hydroxylase phenotype of dopaminergic cells during retina development. 1609 6

The study was aimed at investigating the expression and the activity of neuronal nitric oxide synthase, and of soluble guanylyl cyclase and phosphodiesterase activities that regulate guanosine 3',5'-cyclic monophosphate level in the midbrain, in a mouse model of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections. Adult male mice of the C57/BL strain were given three i.p. injections of physiological saline or three i.p. injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine solution in physiological saline at 2 h intervals (summary 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine dose: 40 mg/kg), and were killed 3, 7, or 14 days later. mRNA, protein level, and/or activities of neuronal nitric oxide synthase, soluble guanylyl cyclase, phosphodiesterase and guanosine 3',5'-cyclic monophosphate were determined. Immunohistochemistry showed about 75% decrease in the number of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine showed increased midbrain guanylyl cyclase and total nitric oxide synthase activities at 3, 7, and 14 days post-treatment. The specific neuronal nitric oxide synthase inhibitor 7-nitroindazole (10 microM) and the specific inducible nitric oxide synthase inhibitor 1400W (10 microM) inhibited the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced excess in nitric oxide synthase activity by 63-70 and 13-25%, respectively. The increases in total midbrain nitric oxide synthase activity were accompanied by elevated guanosine 3',5'-cyclic monophosphate, enhanced expression of neuronal nitric oxide synthase and of the beta1 subunit of guanylyl cyclase at both mRNA and protein levels that persisted up to the end of the observation period, and by enhanced neuronal nitric oxide synthase and guanylyl cyclase beta1 immunoreactivities in substantia nigra pars compacta 7 and 14 days after the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. The increases in guanylyl cyclase activity were found to occur exclusively due to increased maximal enzyme activity. No 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced change in phosphodiesterase activity has been detected in any brain region studied. 7-Nitroindazole prevented a significant increase in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced midbrain guanosine 3',5'-cyclic monophosphate level and neurodegeneration of dopaminergic neurons. These results raise the possibility that the nitric oxide/guanylyl cyclase/guanosine 3',5'-cyclic monophosphate signaling pathway may play a role in maintaining dopaminergic neurons function in substantia nigra pars compacta.
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PMID:Alterations of the expression and activity of midbrain nitric oxide synthase and soluble guanylyl cyclase in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in mice. 1671 28

Noradrenaline is thought to play modulatory roles in a number of physiological, behavioral, and cellular processes. Although many of these modulatory effects are mediated through alpha-1 adrenoceptors, basic knowledge of the cellular and subcellular distributions of these receptors is limited. We investigated the laminar distribution pattern of alpha-1 adrenoceptors in rat visual cortex, using immunohistochemistry at both light and electron microscopic levels. Affinity-purified anti-alpha-1 antibody was confirmed to react only with a single band of about 70-80 kDa in total proteins prepared from rat visual cortex. Alpha-1 adrenoceptors were widely distributed though all cortical layers, but relatively high in density in layers I, II/III, and V. Immunoreactivity was observed in both neuronal perikarya and processes including apical dendrites. In double-labeling experiments with anti-microtubule-associated protein 2, anti-neurofilament, anti-glial fibrillary acidic protein, anti-glutamic acid decarboxylase 65/67, anti-2-3-cyclic nucleotide 3-phosphodiesterase, and anti-tyrosine hydroxylase antibodies, alpha-1 adrenoceptors were found mainly in dendrites and somata of microtubule-associated protein 2-immunopositive neurons. About 20% of alpha-1 adrenoceptors were in GABAergic neurons. A small number of alpha-1 adrenoceptors were also distributed in axons of excitatory neurons, astrocytes, oligodendrocytes and noradrenergic fibers. Using an immunoelectron microscopic technique, numerous regions of alpha-1 adrenoceptor immunoreactivity were found in cell somata, on membranes of dendrites, and in postsynaptic regions. Moreover, a small number of immunoreaction products were also detected in axons and presynaptic sites. These findings provide the first quantitative evidence regarding the cellular and subcellular localization of alpha-1 adrenoceptor immunoreactivity in visual cortex. Moreover, the ultrastructural distribution of alpha-1 adrenoceptor immunoreactivity suggests that alpha-1 adrenoceptors are transported mainly into dendrites and that they exert effects at postsynaptic sites of neurons.
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PMID:Cellular and subcellular localization of alpha-1 adrenoceptors in the rat visual cortex. 1679 31

We investigated the alteration of oligodendrocytes in comparison with that of astrocytes and microglia in the mouse striatum after MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropridine) treatment under the same conditions using Western blot analysis and Immunohistochemistry. In our Western blot analysis, four administrations of MPTP at 2-h intervals to mice produced the remarkable loss of TH (tyrosine hydroxylase) protein levels in the striatum after 3 and 7 days. In contrast, GFAP (glial fibrillary acidic protein) and Iba-1 protein in the striatum showed a significant increase of GFAP and Iba-1 protein levels 3 and 7 days after MPTP treatment. On the other hand, the levels of CNPase (2', 3'-cyclic nucleotide 3'-phosphodiesterase) protein were decreased significantly in the striatum 3 and 7 days after MPTP treatment. In our immunohistochemical study, a significant decrease in the area of expression of CNPase-positive profiles was observed in the striatum 3 and 7 days after MPTP treatment. These results demonstrate that oligodendrocytes in the striatum are damaged after MPTP treatment. Thus our present findings provide valuable information for the pathogenesis of Parkinson's disease.
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PMID:Damage to oligodendrocytes in the striatum after MPTP neurotoxicity in mice. 1767 28

Rolipram, a specific inhibitor of the phosphodiesterase IV (PDE IV), has recently been shown to exert neuroprotective effects in an Alzheimer transgenic mouse model and in hypoxic-ischemic damage in the rat brain. It activates the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway and it inhibits inflammation. We tested the neuroprotective effects of the specific PDE IV inhibitor rolipram in C57BL/6 mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found that rolipram administered at 1.25 mg/kg or 2.5 mg/kg doses significantly attenuated MPTP-induced dopamine depletion in the striatum, and reduced the loss of tyrosine hydroxylase-positive neurons in the substantia nigra. There was a bell-shaped dose effect with greater efficacy at the 1.25 mg/kg dose than 2.5 mg/kg and a higher dose of rolipram, 5 mg/kg, had no protective effect and even increased the mortality of animals when co-administered with MPTP. Rolipram did not interact with MPTP in its absorption into the brain and in its metabolism to 1-methyl-4-phenylpyridinium (MPP(+)). Our data show a neuroprotective effect of the PDE IV specific inhibitor rolipram against dopaminergic neuron degeneration, suggesting that PDE IV inhibitors might be a potential treatment for Parkinson's disease.
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PMID:Attenuation of MPTP neurotoxicity by rolipram, a specific inhibitor of phosphodiesterase IV. 1832 79

Neurons located in the lateral septal organ (LSO) and medial basal hypothalamus (MBH) have been proposed to be encephalic photoreceptors (EPRs), which sense photoperiodic time and initiate avian gonadal development. Controversy continues regarding the location of EPRs serving the PNES and their signal transduction pathway. Using quantitative real-time RT-PCR we determined activation of key genes following prolonged light periods and sulfamethethazine (compound known to advance light-induced testes development) in 21-day old chicks. Earliest activation occurred in genes of vasoactive intestinal polypeptide (VIP) and type 6 phosphodiesterase beta subunit (PDE-6 beta) in the LSO at 4 and 6h, respectively, after onset of light and sulfamethazine intake. In contrast, no change was detected in the MBH during the first 8h of that treatment. Thereafter, significant increases in gonadotropin releasing hormone (GnRH-1) and VIP receptor (VIPR) mRNA transcripts were detected in the bed nucleus of the pallial commissure (NCPa). Hours later, activation of all four genes (VIP, PDE-6 beta, GnRH-1, VIPR) were induced solely by photostimulation. Deiodinase 2 and tyrosine hydroxylase in the MBH did not show increased gene expression until 12h of photostimulation. Prolactin mRNA transcripts showed significant increases at 4h due to SMZ intake and at 24, 36 and 48 h due to long-day photoperiodic effects. Data suggest that VIP neurons in the LSO may serve as EPRs and utilize PDE, present in the phototransduction cascade of known photoreceptors. Additionally, VIP released from the LSO may modulate GnRH-1 neurons in the NCPa via VIP receptors by increasing GnRH-1 gene expression.
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PMID:A possible neural cascade involving the photoneuroendocrine system (PNES) responsible for regulating gonadal development in an avian species, Gallus gallus. 1859 49

Functional evidence suggests that nitric oxide (NO) signalling in the rostral ventrolateral medulla (RVLM) is cGMP-dependent and that this pathway is impaired in hypertension. We examined cGMP expression as a marker of active NO signalling in the C1 region of the RVLM, comparing adult (>18 weeks) Wistar-Kyoto (WKY, n = 4) and spontaneously hypertensive rats (SHR, n = 4). Double label immunohistochemistry for cGMP-immunoreactivity (IR) and C1 neurons [as identified by phenylethanolamine N-methyltransferase (PNMT-IR) or tyrosine hydroxylase TH-IR)], or neuronal NO synthase (nNOS) neurones, failed to reveal cGMP-IR neurons in the RVLM of either strain, despite consistent detection of cGMP-IR in the nucleus ambiguus (NA). This was unchanged in the presence of isobutylmethylxanthine (IBMX; 0.5 mM, WKY, n = 4, SHR n = 2) and in young animals (WKY, 10-weeks, n = 3). Incubation of RVLM-slices (WKY, 10-weeks, n = 9) in DETA-NO (100 mum; 10 min) or NMDA (10 muM; 2 min) did not uncover cGMP-IR. In all studies, cGMP was prominent within the vasculature. Soluble guanylate cyclase (sGC)-IR was found throughout neurones of the RVLM, but did not co-localise with PNMT, TH or nNOS-IR neurons (WKY, 10-weeks, n = 6). Results indicate that within the RVLM, cGMP is not detectable using immunohistochemistry in the basal state and cannot be elicited by phosphodiesterase inhibition, NMDA receptor stimulation or NO donor application.
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PMID:Immunohistochemical assessment of cyclic guanosine monophosphate (cGMP) and soluble guanylate cyclase (sGC) within the rostral ventrolateral medulla. 1860 39


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