Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of the negative control of tyrosine hydroxylase (TH) activity induced by the stimulation of presynaptic 3,4-dihydroxyphenylethylamine (dopamine, DA) autoreceptors was investigated using rat striatal slices and synaptosomes incubated under control ([ K+] = 4.8 mM) or depolarizing ([ K+] = 60 mM) conditions. The stimulation of DA autoreceptors by 7-hydroxy-2-(di-n-propylamino)tetralin (1 microM 7-OH-DPAT) produced a significant decrease in TH activity extracted from striatal slices maintained under control conditions. This effect was associated with the complete conversion of TH into an enzyme form with a low affinity for its pterin cofactor (Km approximately 0.80 mM). Furthermore, compared to TH extracted from control tissues, that from 7-OH-DPAT-exposed striatal slices was more sensitive to the stimulatory effects of exogenous heparin and cyclic AMP-dependent phosphorylation. Such changes were opposite to those induced by incubating striatal slices with the adenylate cyclase activator forskolin. Indeed, forskolin treatment completely converted TH into an enzyme form with a high affinity for its pterin cofactor (Km approximately 0.16 mM). Such conversion was associated with a shift in the optimal pH for TH activity from 5.8 (control) to 7.2 (forskolin). Under depolarizing conditions, the blockade by (-)-sulpiride of the stimulation of DA autoreceptors by endogenous DA was associated with a marked activation of TH. Modifications of enzymatic characteristics triggered by (-)-sulpiride were then similar to those induced by forskolin treatment. These data suggest that presynaptic DA autoreceptors modulate the activity of TH by controlling the degree of cyclic AMP-dependent phosphorylation of the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Is dopamine-induced inhibition of adenylate cyclase involved in the autoreceptor-mediated negative control of tyrosine hydroxylase in striatal dopaminergic terminals? 287 53

Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, is subject to regulation by a variety of agents. Previous workers have found that cyclic AMP-dependent protein kinase and calcium-stimulated protein kinases activate tyrosine hydroxylase. We wanted to determine whether cyclic GMP might also be involved in the regulation of tyrosine hydroxylase activity. We found that treatment of rat PC12 cells with sodium nitroprusside (an activator of guanylate cyclase), 8-bromocyclic GMP, forskolin (an activator of adenylate cyclase), and 8-bromocyclic AMP all produced an increase in tyrosine hydroxylase activity measured in vitro or an increased conversion of [14C]tyrosine to labeled catecholamine in situ. Sodium nitroprusside also increased the relative synthesis of cyclic GMP in these cells. In the presence of MgATP, both cyclic GMP and cyclic AMP increased tyrosine hydroxylase activity in PC12 cell extracts. The heat-stable cyclic AMP-dependent protein kinase inhibitor failed to attenuate the activation produced in the presence of cyclic GMP. It eliminated the activation produced in the presence of cyclic AMP. Sodium nitroprusside also increased tyrosine hydroxylase activity in vitro in rat corpus striatal synaptosomes and bovine adrenal chromaffin cells. In all cases, the cyclic AMP-dependent activation of tyrosine hydroxylase was greater than that of the cyclic GMP-dependent second messenger system. These results indicate that both cyclic GMP and cyclic AMP and their cognate protein kinases activate tyrosine hydroxylase activity in PC12 cells.
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PMID:Activation of tyrosine hydroxylase in PC12 cells by the cyclic GMP and cyclic AMP second messenger systems. 287 73

Incubation of rat pheochromocytoma PC12 cells with 4 beta-phorbol-12 beta-myristate-13 alpha-acetate (PMA), an activator of Ca2+/phospholipid-dependent protein kinase (protein kinase C), or forskolin, an activator of adenylate cyclase, is associated with increased activity and enhanced phosphorylation of tyrosine hydroxylase. Neither the activation nor increased phosphorylation of tyrosine hydroxylase produced by PMA is dependent on extracellular Ca2+. Both activation and phosphorylation of the enzyme by PMA are inhibited by pretreatment of the cells with trifluoperazine (TFP). Treatment of PC12 cells with 1-oleoyl-2-acetylglycerol also leads to increases in the phosphorylation and enzymatic activity of tyrosine hydroxylase; 1,2-diolein and 1,3-diolein are ineffective. The effects of forskolin on the activation and phosphorylation of the enzyme are independent of Ca2+ and are not inhibited by TFP. Forskolin elicits an increase in cyclic AMP levels in PC12 cells. The increases in both cyclic AMP content and the enzymatic activity and phosphorylation of tyrosine hydroxylase following exposure of PC12 cells to different concentrations of forskolin are closely correlated. In contrast, cyclic AMP levels do not increase in cells treated with PMA. Tryptic digestion of the phosphorylated enzyme isolated from untreated cells yields four phosphopeptides separable by HPLC. Incubation of the cells in the presence of the Ca2+ ionophore ionomycin increases the phosphorylation of three of these tryptic peptides. However, in cells treated with either PMA or forskolin, there is an increase in the phosphorylation of only one of these peptides derived from tyrosine hydroxylase. The peptide phosphorylated in PMA-treated cells is different from that phosphorylated in forskolin-treated cells. The latter peptide is identical to the peptide phosphorylated in dibutyryl cyclic AMP-treated cells. These results indicate that tyrosine hydroxylase is activated and phosphorylated on different sites in PC12 cells exposed to PMA and forskolin and that phosphorylation of either of these sites is associated with activation of tyrosine hydroxylase. The results further suggest that cyclic AMP-dependent and Ca2+/phospholipid-dependent protein kinases may play a role in the regulation of tyrosine hydroxylase in PC12 cells.
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PMID:Tyrosine hydroxylase is activated and phosphorylated on different sites in rat pheochromocytoma PC12 cells treated with phorbol ester and forskolin. 288 80

Incubation of rat striatal synaptosomes with the adenosine receptor agonist 2-chloroadenosine (2-CADO) produced a concentration-dependent increase of dopamine (DA) synthesis (about 50% of control value). The effect was not additive with the stimulation produced by either 10 microM forskolin or 2 mM dibutyryl cyclic AMP. Pretreatment of striatal synaptosomes with 2-CADO produced an activation of tyrosine hydroxylase (TH) which withstood washing and lysing of the tissue. This activation was largely independent of the presence of Ca2+ ion in the preincubation medium and, when analyzed as a function of different concentrations of the pterin cofactor 6-methyl-5,6,7,8-tetrahydropterin (0.08-0.4 mM), it was associated with an apparent increase in the Vmax of the enzyme. Quinpirole, a selective D2 DA receptor agonist, reduced control synaptosomal DA synthesis and caused a persistent inhibition of TH activity. When added together with 2-CADO, quinpirole depressed the stimulation of DA synthesis and TH activity produced by the adenosine analog. The effect of quinpirole was stereospecifically antagonized by the D2 DA antagonist sulpiride. Quinpirole also inhibited the activation of TH elicited by a submaximal concentration of forskolin, but not that produced by dibutyryl cyclic AMP. The inhibitory effect of quinpirole on basal and 2-CADO-stimulated TH activities was mimicked by DA. These results indicate that presynaptic DA autoreceptors and adenosine A2 receptors interact antagonistically in controlling DA synthesis in rat striatal synaptosomes presumably by exerting opposite inputs on a presynaptic adenylate cyclase system.
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PMID:Evidence that adenosine A2 and dopamine autoreceptors antagonistically regulate tyrosine hydroxylase activity in rat striatal synaptosomes. 290 90

The central dopaminergic effects of an abeorphine derivative 201-678 were compared to those of apomorphine and bromocriptine in different model systems. After oral administration, this compound induced contralateral turning in rats with 6-hydroxydopamine induced nigral lesions and exhibited strong anti-akinetic properties in rats with 6-hydroxydopamine induced hypothalamic lesions. It decreased dopamine metabolism in striatum and cortex, but did not modify noradrenaline and serotonin metabolism in the rat brain. 201-678 counteracted the in vivo increase of tyrosine hydroxylase activity induced by gamma-butyrolactone. In vitro it stimulated DA-sensitive adenylate cyclase and inhibited acetylcholine release from rat striatal slices. This compound had high affinity for 3H-dopamine and 3H-clonidine binding sites. These results indicate that 201-678 is a potent, orally active dopamine agonist with a long duration of action. Furthermore it appears more selective than other dopaminergic drugs.
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PMID:Pharmacological profile of the abeorphine 201-678, a potent orally active and long lasting dopamine agonist. 300 74

Many hormones and neurotransmitters exert their biological effects by increasing the levels of Ca2+ and 1,2-diacylglycerol in their target cells. Major agonists that act in this way are epinephrine and norepinephrine, acetylcholine, vasopressin, cholecystokinin, and angiotensin II. These and other Ca2+-mobilizing agonists may also produce effects that are not mediated by Ca2+ or diacylglycerol, but involve separate receptors and an increase or decrease in cyclic AMP. The general mechanisms by which Ca2+-mobilizing agonists induce their physiological responses are depicted in Fig. 12. These responses appear to involve an initial mobilization of Ca2+ from endoplasmic reticulum and perhaps other intracellular Ca2+ stores, followed by alterations in the flux of Ca2+ across the plasma membrane. The Ca2+ changes are consistently associated with increased turnover of cellular phosphoinositides. The most rapid response is breakdown of phosphatidylinositol 4,5-P2 in the plasma membrane, and there is much evidence that this involves a guanine-nucleotide-binding regulatory protein similar to those involved in the regulation of adenylate cyclase. Myo-inositol 1,4,5-P3 produced by phosphatidylinositol 4,5-P2 breakdown rapidly releases Ca2+ from endoplasmic reticulum, and it is likely that it is the long-sought second message for the Ca2+-dependent hormones. 1,2-Diacylglycerol, the other product of phosphatidylinositol 4,5-P2 breakdown, also acts as a second message in that it activates protein kinase C, a Ca2+-phospholipid-dependent protein kinase, by lowering its requirement for Ca2+. The cellular substrates for protein kinase C and its role in the different physiological responses to the Ca2+-mediated agonists are currently being defined. The major intracellular target for Ca2+ is the Ca2+-dependent regulatory protein calmodulin. This binds Ca2+ with high affinity, and the resulting complex interacts with a variety of enzymes and other cellular proteins, modifying their activities. A major target is the multifunctional calmodulin-dependent protein kinase that phosphorylates and alters the activities of many proteins, for example, glycogen synthase and tyrosine hydroxylase. Calcium ions may also stimulate calmodulin-dependent protein kinases that are more specific, such as phosphorylase kinase and myosin light-chain kinase. Other important Ca2+-calmodulin targets are the microtubule-associated proteins, but it is likely that many more will be found.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms involved in calcium-mobilizing agonist responses. 302 85

We have identified a new subline of PC12 pheochromocytoma cells (PC12D cells) in which neurites are extended within 24 hr in response to cAMP-enhancing reagents as well as in response to nerve growth factor (NGF), but not in response to epidermal growth factor or phorbol diester. Anti-NGF antiserum did not affect forskolin (FRK)-induced neuritic recruitment. FRK-induced neurites exhibited growth cones and contained secretion granules and many parallel arrays of microtubules as was the case with NGF-induced neurites. FRK, but not NGF, increased the levels of intracellular cAMP and activated adenylate cyclase in the membrane fraction. Both NGF and FRK enhanced the activities of tyrosine hydroxylase (TH), acetylcholinesterase (AchE), and ornithine decarboxylase (ODC), but not the levels of neuron-specific enolase. Enhanced levels of intracellular cAMP mimicked the effects of NGF on neuritic growth, TH, AchE, and ODC activities in PC12D cells, even though NGF does not act through elevation of levels of cAMP.
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PMID:Neuritic growth from a new subline of PC12 pheochromocytoma cells: cyclic AMP mimics the action of nerve growth factor. 303 56

The influence of 2-(2-oxo-3-piperidyl)-1,2-benzisothiazoline-3-one-1, 1-dioxide (supidimide), a representative of a new class of sedative drugs, on the noradrenergic, dopaminergic, serotoninergic and gamma-aminobutyric acid (GABA)ergic neuronal systems of rodent brains was investigated. In each case the brain transmitter levels after administration of supidimide were determined. Utilisation of noradrenaline (norepinephrine, NE), dopamine (DA), and 5-hydroxytryptamine (5-HT) was also investigated ex vivo. The study was complemented with in vitro investigations of biosynthesis, synaptosomal uptake, degradation, and receptor binding of the transmitters. Based on a preliminary study of the distribution of [35S]-supidimide in rat brain, in vitro effects observed at greater than 10(-4) mol/l were considered irrelevant. Similarly, in vivo effects requiring dosages higher than 300 mg/kg i.p. were not regarded adequate to explain the sedative and antiaggressive efficacy of supidimide. With the above restrictions, the following parameters can be rated as not influenced by supidimide: levels of tryptophan in rat brain and serum (free and total); 5-HT biosynthesis in vivo (rat brain; 5-HT accumulation after monoamine oxidase (MAO) blockade); activity of MAO-A and MAO-B (rat brain mitochondria); uptake of 5-HT, NE and DA (rat synaptosomes); 5-HT receptor binding ( [3H]-LSD binding assay in rat cortical membranes); tyrosine hydroxylase activity (rat adrenal glands); catechol-O-methyl transferase (COMT) (rat liver); NE binding to central alpha 1- and alpha 2-receptors (rat brain; radioligand assay with [3H]-dihydroergocryptine, [3H]-prazosin and [3H]-WB 4101 (2',6'-dimethoxy-(G-3H]-phenoxy]-ethylaminomethylbenzo-1,4-dioxane ); DA levels (whole rat brain and striata); dihydroxyphenylacetic acid (DOPAC) levels (whole rat brain without cerebellum and striata); elevated DOPAC levels after pretreatment with haloperidol; DA-dependent adenylate cyclase in vitro (rat striatum); D2 receptor binding ( [3H]-spiperone binding assay, rat striatum); GABA levels (mouse brain); GABA transaminase activity (mouse brain stem); sodium-independent [3H]-GABA receptor binding (rat brain) and benzodiazepine binding (rat cortical membranes, [3H]-diazepam binding assay). Two effects on the GABAergic system were induced by supidimide. Starting at 300 mg/kg i.p., supidimide slowed down the GABA accumulation in brains of aminooxyacetate-treated mice. At 10(-4) mol/l supidimide caused a significant inhibition of GABA uptake (rat synaptosomes).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Influence of supidimide on brain neurotransmitter systems of rats and mice. 608 11

Tyrosine hydroxylase (TH) activity is increased two- to threefold in neuroblastoma cell line NBP2 maintained in culture for 48 h in the presence of either the inhibitor of cyclic AMP-phosphodiesterase (PDE), 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO 20-1724), or the activator of adenylate cyclase, prostaglandin E1 (PGE1). Cyclic AMP levels are elevated 70-80% and 30-40% throughout the 48-h treatment with RO 20-1724 and PGE1, respectively. Carbachol does not affect either basal TH activity or cyclic AMP levels in the cells. However, the cholinergic agonist delays the induction of TH elicited by either RO 20-1724 or PGE1. This delay is prevented by atropine. The elevation in cyclic AMP levels elicited by either RO 20-1724 or PGE1 is blocked for 1 h or 15 min, respectively, after treatment with carbachol. Cyclic AMP levels then begin to rise until they reach those levels observed in the presence of RO 20-1724 or PGE1 alone by 12 h or 1 h of treatment, respectively. Time course studies demonstrate that this transient inhibition of the elevation of cyclic AMP is associated with a 48-h delay in the induction of TH elicited by either RO 20-1724 or PGE1. In contrast, the induction elicited by 8-bromo cyclic AMP is unaffected by carbachol. A depolarizing concentration (56 mM) of KCl produces a 24-h delay in the induction of TH elicited by RO 20-1724, without affecting the concomitant elevation of cyclic AMP produced by the PDE inhibitor. Furthermore, 56 mM-KCl inhibits the induction of TH elicited by 8-bromo cyclic AMP. It thus appears that carbachol delays the induction of TH by transiently inhibiting the elevation of cyclic AMP, whereas potassium depolarization delays the induction of TH by inhibiting a process with a site of action that is distal to the elevation of cyclic AMP.
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PMID:Effect of carbachol and 56 mm-potassium chloride on the cyclic AMP-mediated induction of tyrosine hydroxylase in neuroblastoma cells in culture. 610 63

Considerable evidence has accumulated in recent years to suggest that cyclic AMP-dependent protein kinase is responsible for the activation of tyrosine hydroxylase following nerve stimulation. Since stimulation of the central nervous system either by electrical impulses or by exposure of intact brain tissue to depolarizing concentrations of potassium is associated with an activation of adenylate cyclase and an increase in cyclic AMP, it is possible that the normal physiological mechanism by which catecholamine synthesis is enhanced during nerve stimulation involves modification of the enzyme by protein kinase. It has been demonstrated that, in the presence of cyclic AMP, ATP, Mg++ and protein kinase, purified preparations of tyrosine hydroxylase are directly phosphorylated. Since cyclic nucleotides also have been implicated in the process of neurally mediated transmitter release, it is conceivable that activation of adenylate cyclase presynaptically is a common mechanism by which both catecholamine synthesis and norepinephrine release are enhanced during nerve stimulation. Although agonists and antagonists of many putative presynaptic receptors have been found to modulate norepinephrine release during nerve stimulation, no convincing evidence has yet been obtained to suggest that alteration of presynaptic adenylate cyclase activity consequent to nerve stimulation is mediated by a presynaptic action of one or more of these neuromodulators. It is possible that direct depolarization of the nerve terminal in some manner results in activation of presynaptic adenylate cyclase, perhaps by a mechanism involving calcium.
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PMID:The participation of cyclic nucleotides and protein kinase in the regulation of norepinephrine synthesis and release during nerve stimulation. 611 2


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