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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In primary cultured bovine adrenal chromaffin cells (BACC), pituitary adenylate cyclase activating polypeptide 1-38 (PACAP) produced a dose related increase in tyrosine hydroxylase (TH) Vmax when measured 48 hours after the beginning of the treatment; a significant increase was observed with 0.5 nM and the maximal induction of close to 2.5-fold was found with 0.1 microM PACAP. The potency of PACAP was nearly 3 orders of magnitude greater than forskolin and VIP in inducing TH activity. These effects were preceded by an increase in TH mRNA levels, that started 2 hours after treatment and peaked 12 hours later. The presence of the phosphodiesterase inhibitor HL 725 further increased the stimulation of TH activity by PACAP, indicating that this activation was mediated via a cascade of events initiated by cAMP. Nicotine (1 microM) failed to increase TH activity significantly, however, when added in association with PACAP, a statistically significant increase of TH was elicited with peptide concentrations 5 times lower (0.1 nM) than the threshold dose of the peptide. The stimulation of nicotinic receptors facilitates the TH induction elicited by PACAP.
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PMID:Pituitary adenylate cyclase activating polypeptide (PACAP) potently enhances tyrosine hydroxylase (TH) expression in adrenal chromaffin cells. 790 10

Pituitary adenylate cyclase-activating polypeptide (PACAP)i a potent stimulant of catecholamine secretion, increased catecholamine production in cultured porcine adrenal medullary chromaffin cells. PACAP induced dose-and time-dependent increases in mRNAs for the catecholamine synthesizing enzymes, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH), with maximal 6- and 4-fold increases occurring at 8-16 h, respectively. The half-maximally and maximally effective PACAP concentrations for stimulation of TH and DBH gene expression were 0.5 and 3 nM, respectively. The TH protein level also showed an increase over the unstimulated basal level at 16-24 h in PACAP-stimulate cells. We previously demonstrated that PACAP activates both phospholipase C and adenylate cyclase in adrenal medullary cells. Addition of forskolin alone induced increases in mRNA expression of both TH and DBH. The phosphodiesterase inhibitor 3- isobutyl-1-methylxanthine potentiated the induction of TH and DBH mRNAs by PACAP. Addition of the protein kinase C activator phorbol 12-myristate 13-acetate (PMA) also caused increases in TH and DBH mRNA levels. In protein kinase C-downregulated cells pretreated with PMA for 24 h, the stimulatory effect of PACAP on TH and DBH gene expression was diminished. These results suggest that cAMP and protein kinase C mediate the PACAP-induced TH and DBH gene expression. Removal of extracellular Ca2+ with EGTA enhanced the PACAP-induced increases in both cellular cAMP and mRNA levels of TH and DBH, suggesting that Ca2+ has an inhibitory effect on the induction of TH and DBH mRNAs. In conclusion, the present study indicates that PACAP coordinately upregulates the gene expression of both TH and DBH by activating the cAMP and protein kinase C signaling pathways, leading to simulation of cate-cholamine synthesis, while Ca2+ negatively regulates TH and DBH gene expression in porcine adrenal medullary cells.
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PMID:Pituitary adenylate cyclase-activating polypeptide induces gene expression of the catecholamine synthesizing enzymes, tyrosine hydroxylase and dopamine beta hydroxylase, through 3',5'-cyclic adenosine monophosphate- and protein kinase C-dependent mechanisms in cultured porcine adrenal medullary chromaffin cells. 877 59

Transcriptional regulation of the rat tyrosine hydroxylase (TH) gene by prostaglandin E2 (PGE2) was investigated in human neuroblastoma SK-N-BE(2)C cells. Prostaglandins increased intracellular cAMP in the presence of 3-isobutyl-1-methylxanthine (IBMX), a cAMP phosphodiesterase inhibitor. Among the prostaglandins tested for their cAMP raising property PGE2 was the most effective. The results suggest that the cells express adenylyl cyclase-linked prostanoid receptors that have a higher affinity for PGE2 than for any other naturally occurring prostaglandin. The treatment of cells with PGE2 increased the TH gene expression approximately 2-fold, even though the cAMP accumulation induced by PGE2 alone was almost negligible. Simultaneous treatment with PGE2 and IBMX enhanced the gene expression concomitantly with a marked accumulation of cAMP. Transient transfection assays with 5' upstream serially deleted constructs of the rat TH gene promoter region fused to the chloramphenicol acetyltransferase (CAT) gene revealed that a cAMP response element (CRE) located at -45 to -38 from the start of the TH gene was essential for the enhancement of TH gene expression by PGE2. Site-directed mutagenesis and specific deletion within the sequence of the CRE motif abolished the transcriptional enhancement by PGE2. In addition, a protein kinase A (PKA) inhibitor, H89, specifically blocked the PGE2 effect on TH gene expression. Northern blot analysis revealed that the increase in TH gene transcription with PGE2 is associated with an elevated TH mRNA level. Gel retardation and competition assays confirmed that the binding of nuclear factors to the CRE site was sequence specific and was augmented by PGE2. Our data indicate that PGE2 enhances transcription of the TH gene mediated by the CRE motif through the activation of PKA. They also suggest that the signal flow from the adenylyl cyclase-linked prostanoid receptor to the nucleus is efficient although cAMP accumulation is not prominent.
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PMID:Transcriptional enhancement of tyrosine hydroxylase by prostaglandin E2 in SK-N-BE(2) C cells. 880 26

The neuropathology of Parkinson's disease is characterized by the degeneration of dopaminergic neurons in the substantia nigra. We have recently shown that the activation of protein kinase A improves the survival of dopaminergic neurons in culture and, furthermore, protects them from the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP+) in vitro. We have now analysed the potential of phosphodiesterase inhibitors to increase cAMP levels in dopaminergic neurons, to improve their survival in culture and to protect them from the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in vivo. Increasing intracellular cAMP with phosphodiesterase type IV-specific inhibitors enhanced the survival of dopaminergic neurons in culture. Inhibitors of other phosphodiesterase types were not active. In vivo, phosphodiesterase type IV inhibitors reduced the MPTP-induced dopamine depletion in the striatum of C57BL/6 mice. Furthermore, the loss of tyrosine hydroxylase-immunopositive neurons in the substantia nigra of these animals was diminished. After Nissl staining, a similar reduction of the MPTP-induced loss of neurons was observed in the substantia nigra. The protective effect of protein kinase A activation did not appear to be due to the blocking of MPP+ uptake into dopaminergic neurons. This was not decreased after treatment with forskolin or 8-(4-chlorophenylthio)-cAMP. Thus, protein kinase A regulates the survival and differentiation of dopaminergic substantia nigra neurons in vivo, implicating a therapeutic potential for substances which regulate cAMP turnover in these neurons.
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PMID:Inhibitors of type IV phosphodiesterases reduce the toxicity of MPTP in substantia nigra neurons in vivo. 884 48

Using organotypic cultures of rat ventral mesencephalon, the effects of chronic (12-15 day) exposure to the type IV cAMP phosphodiesterase inhibitor, Ro20-1724, were examined. At concentrations of 10(-8)-10(-5) M, Ro20-1724 alone had no effect upon the number of tyrosine hydroxylase-positive neurons or upon neurite outgrowth. However, the drug offered significant protection, with maximum effect at 10(-6) M, against subsequent acute (48 h) exposure to the neurotoxic agents 1-methyl-4-phenylpyridinium (MPP+) and N-methyl-D-aspartate (NMDA).
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PMID:Chronic exposure to Ro20-1724 protects dopaminergic neurons in vitro against the neurotoxic action of N-methyl-D-aspartate and 1-methyl-4-phenylpyridinium. 912 21

Antibodies raised to phosphorylated forms of tyrosine hydroxylase, the first and rate-limiting enzyme in the catecholamine biosynthesis, were applied in immunohistochemical studies on rat brain slices incubated in vitro with a phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine, IBMX) and on forskolin on formalin-perfused rat brains. Four antisera/antibodies were used: polyclonal rabbit antisera to (i) tyrosine hydroxylase phosphorylated at serine 40 (THS40p antiserum), (ii) tyrosine hydroxylase phosphorylated at serine 19 (THS19p antiserum), (iii) the native enzyme (pan-tyrosine hydroxylase antiserum), and mouse monoclonal antibody to (iv) native tyrosine hydroxylase. In the in vitro studies THS40p-like immunoreactivity was not observed unless slices were treated with IBMX-forskolin after which a dense fibre network was found in the striatum, and immunoreactive cell bodies were found in the ventral mesencephalon, especially in the ventral tegmental area. Although these cells were pan-tyrosine hydroxylase-positive, several of them were not stained with the tyrosine hydroxylase-monoclonal antibody. Moreover, there was a marked reduction of tyrosine hydroxylase-monoclonal antibody-immunoreactive fibres in drug-treated slices, suggesting that this tyrosine hydroxylase-monoclonal antibody does not recognize the serine 40-phosphorylated form of tyrosine hydroxylase. Treated slices did not show any THS40p-immunoreactive cell bodies in the dopaminergic A11 cell group and only a few, weakly fluorescent neurons were observed in locus coeruleus. However, a sparse fibre plexus was observed in locus coeruleus, possibly reflecting epinephrine fibres. In the perfused brains THS40p-like immunoreactivity could be visualized in some dopamine neurons in the ventral mesencephalon, especially the A10 area, and in noradrenergic locus coeruleus neurons, whereas THS19p-like immunoreactivity was found in all catecholamine groups studied, similar to the results obtained with the pan-tyrosine hydroxylase antiserum and the tyrosine hydroxylase-monoclonal antibody. In forebrain areas known to be innervated by mesencephalic dopamine neurons, no THS40p-positive fibres were observed, whereas THS19p-immunoreactive fibres were found in subregions of the striatum, olfactory tubercle and nucleus accumbens, essentially overlapping with dopamine fibres previously shown to contain cholecystokinin-like immunoreactivity. The present results suggests that antibodies directed against phosphorylated forms of tyrosine hydroxylase can be used to evaluate the state of tyrosine hydroxylase phosphorylation in individual neuronal cell bodies and processes both in vitro and in vivo.
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PMID:Immunohistochemical studies on phosphorylation of tyrosine hydroxylase in central catecholamine neurons using site- and phosphorylation state-specific antibodies. 948 31

Cell adhesion molecules play a central role in neural development and are also critically involved in axonal regeneration and synaptic plasticity in the adult nervous system. We investigated whether the neural cell adhesion molecule L1 was capable of stimulating survival and differentiation in the mid-brain dopaminergic neurons which degenerate in Parkinson's disease. Monoclonal L1 antibodies, known to enhance neurite outgrowth, were substrate-coated or added at the time of plating to medium of cultures containing mid-brain dopaminergic neurons from 14-day-old fetal rats. Tritiated dopamine uptake per well and the number of tyrosine hydroxylase-immunopositive neurons increased in a dose-dependent manner with increasing concentrations of L1 antibody, suggesting that L1 acts directly or indirectly as a growth factor for dopaminergic neurons. A monoclonal L1 antibody not enhancing neurite outgrowth was ineffective. The growth-promoting effects of L1 antibodies on dopaminergic neurons in culture did not appear to be mediated by the cAMP-activated protein kinase A pathway, since combined treatment with a phosphodiesterase inhibitor had only additive effects on the L1-induced increase of dopamine uptake, and in addition, antibodies against L1 failed to protect cultures of dopaminergic neurons against the neurotoxin MPP+, whereas pretreatment with forskolin and phosphodiesterase type-IV inhibitors was strongly protective.
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PMID:L1 neural cell adhesion molecule is a survival factor for fetal dopaminergic neurons. 967 69

A study was carried out on the effects on sleep of rolipram, an antidepressant that increases the availability of cAMP by inhibiting a phosphodiesterase isoenzyme. Rats were treated with rolipram (0.1 or 1 mg/kg) twice a day (at light and dark onset) for 11 days, after a chronic period of injection of physiological saline for habituation purposes. The sleep-wake activity was recorded for 12 h following the injection at light onset on the baseline day (physiological saline), on rolipram days 1, 5, and 11, and also on day 12, when physiological saline was injected again (withdrawal day). The high (1 mg/kg) dose of rolipram enhanced wakefulness (W) in postinjection h 1 on day 1 of rolipram treatment. After administration of 0.1 mg/kg rolipram, only a tendency to an increase in W was noted. The promotion of W might be attributed, at least in part, to an increased release of noradrenaline due to a cAMP-mediated stimulation of tyrosine hydroxylase.
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PMID:Rolipram, an antidepressant that increases the availability of cAMP, transiently enhances wakefulness in rats. 970 Sep 66

The olfactory cyclic nucleotide-gated channel subunit 1 (OCNC1) is required for signal transduction in olfactory receptor cells. To further investigate the role of this channel in the olfactory system, the biochemical and morphological consequences of targeted disruption of OCNC1 were investigated in adult mice. Null as compared to wild-type mice had smaller olfactory bulbs, suggesting compromised development of the central target of the receptor cells. Ectopic olfactory marker protein (OMP)-stained fibers localized to the external plexiform layer reflected the relative immaturity of the olfactory bulb in the null mice. The olfactory epithelium of the knock-out mouse was thinner and showed lower expression of olfactory marker protein and growth-associated protein 43, indicating decreases in both generation and maturation of receptor cells. Tyrosine hydroxylase (TH) expression in the olfactory bulb, examined as a reflection of afferent activity, was reduced in the majority of periglomerular neurons but retained in atypical or "necklace" glomeruli localized to posterior aspects of the olfactory bulb. Double label studies demonstrated that the remaining TH-immunostained neurons received their innervation from a subset of receptor cells previously shown to express a phosphodiesterase that differs from that found in most receptor cells. These data indicate that expression of OCNC1 is required for normal development of the olfactory epithelium and olfactory bulb. The robust expression of TH in some periglomerular cells in the OCNC1-null mice suggests that receptor cells innervating these glomeruli may use an alternate signal transduction pathway.
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PMID:Targeted deletion of a cyclic nucleotide-gated channel subunit (OCNC1): biochemical and morphological consequences in adult mice. 1053 36

Pituitary adenylate cyclase-activating polypeptide (PACAP-27) was incubated in a tyrosine hydroxylase (TyrOH) assay with a homogenate preparation of the nucleus accumbens of the rat. TyrOH activity was determined in vitro by measuring the production of L-dopa with HPLC-ECD. Only in the presence of adenosine nucleotides (ATP, App(NH)p) PACAP-27 increased TyrOH activity with a EC(50)of 100 nM. Since the PACAP-27 effect on TyrOH was abolished when homogenate or pellet of the nucleus accumbens were coincubated with CHAPS, the peptide effect appears to be receptor mediated. TyrOH activation produced by PACAP-27 increased in the presence of the phosphodiesterase inhibitor papaverine indicating the involvement of cAMP. The marked effect of the non-hydrolysable adenosine nucleotide App(NH)p also supports a cAMP-dependent TyrOH activation not related to ADP or an ADP-dependent mechanism. This report's data suggest that PACAP-27 activates TyrOH in the rat nucleus accumbens through receptor-mediated cAMP formation. The exact receptor type present in the nucleus accumbens has yet not been specified.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP-27) enhances tyrosine hydroxylase activity in the nucleus accumbens of the rat. 1065 30


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