Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nuclear proto-oncogene, c-fos, has been implicated in the coordinated regulation of gene expression during cell proliferation and differentiation. In this study, we have demonstrated the induction of the c-fos gene products in differentiated cells of the adrenal medulla by non-mitogenic signals. Activation of adrenal medullary cells in vivo by insulin-induced hypoglycemia, and in vitro by nicotine or angiotensin resulted in the rapid and transient elevation of c-fos mRNA levels. Induction of the c-fos mRNA by angiotensin and nicotine were accompanied by the appearance of the c-fos protein. The increase in c-fos protein occurred initially in the cytoplasm and, later, in the nucleus, and it was co-localized with tyrosine hydroxylase. Nuclear expression of the c-fos protein was also induced by veratridine, forskolin and the calcium ionophore A231287. The role of calcium in the regulation of the c-fos gene by angiotensin with nifedipine and inhibition of the effects of angiotensin with nifedipine and sphingosine, a protein kinase C inhibitor. Activation of the c-fos gene may play a role in the coordinated induction of genes involved in the long-term adaptation of adrenal medullary cells to increased functional demands.
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PMID:Stimulation of adrenal medullary cells in vivo and in vitro induces expression of c-fos proto-oncogene. 210 3

Stimulation of cultured bovine chromaffin cells with histamine (10(-5) M), nicotine (10(-6) M), and veratridine (2 x 10(-6) M) results in a time-dependent up to 5-fold increase in proenkephalin (Penk) mRNA levels. After an initial lag phase (with no major alterations) Penk mRNA increased markedly between 6 and 12 h followed by a slower, steady increase up to 48 h. The nicotinic receptor antagonist tubocurarine (4 x 10(-7) M) and the Ca2+ channel blocker D600 (10(-5) M) prevent the subsequent rise of Penk mRNA levels after challenge with nicotine, when given within the lag phase (0-6 h), suggesting the need of continuous receptor occupation and Ca2+ entry for induction of gene expression. Similarly, incubation of chromaffin cells with cycloheximide (10(-6) M), given at 0-6 h, blocks the increase in Penk mRNA after stimulation with histamine and nicotine indicating that ongoing protein synthesis is necessary for the delayed rise of Penk mRNA. Nuclear run-off experiments revealed high transcription levels of the Penk gene (3-fold at 2 h) and the tyrosine hydroxylase gene (7-fold at 20 min) following stimulation with histamine, which was not observed in the presence of cycloheximide (10(-5) M). A more rapid induction of transcription was measured for the c-fos gene after histamine stimulation (high levels after 12 min) followed by c-fos mRNA accumulation (about 20-fold after a 1-h stimulation), which was superinduced when cells were pretreated with cycloheximide. The half-life of Penk mRNA levels (about 12 h), however, seems not to be affected by histamine as suggested by measurement of the subsequent decay of Penk mRNA levels after addition of alpha-amanitin or alpha-amanitin and cycloheximide. Thus, activation of Penk gene expression upon neurotransmitter challenge is suggested to be due to an enhanced transcriptional activity of the gene mediated by de novo synthesized protein (-like) factors.
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PMID:Mechanisms involved in the transcriptional activation of proenkephalin gene expression in bovine chromaffin cells. 222 66

Dopamine (DA) levels in the various brain regions of epileptic mice (El mice) were compared immunohistochemically with those in ddY mice (the mother strain of El mice) using a fluorescence microphotometry system. The fluorescence intensities of DA in the neostriatum and nucleus accumbens septi in El mice were approximately 11-15% (P less than 0.01) and 13% (P less than 0.01) lower than in ddY mice. On the other hand, the lower DA amounts in these regions of El mice were improved by intraventricular administration of CaCl2 (10 mumol/kg). The brain regions in which the amount of DA was increased by calcium were areas where high levels of calmodulin and tyrosine hydroxylase are distributed. This finding reconfirmed our previous report that the biogenic amine level disorder in El mice was related to a calcium ion level disorder through a central calcium-calmodulin-dependent biogenic amine-synthesizing mechanism, and this might increase their susceptibility to epileptic convulsions.
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PMID:Effect of intraventricular administration of calcium on the lowering of brain dopamine level in epileptic mice. 227 43

The expression of the vesicular monoamine transporter was studied in newborn rat sympathetic neurons and compared to that of the catecholamine biosynthesis enzymes tyrosine hydroxylase and dopamine-beta-hydroxylase. The vesicular monoamine transporter was assayed using the specific ligand [3H]dihydrotetrabenazine. In cultures grown for 10 days in the presence of 35 mM K+, tyrosine hydroxylase activity and the density of [3H]dihydrotetrabenazine binding sites were increased by a similar 2-3-fold factor, while dopamine-beta-hydroxylase activity and protein level were unchanged. Under these conditions, choline acetyltransferase activity was depressed by 90%. The induction of the vesicular monoamine transporter by high K+ was dependent upon Ca2+ entry through slow calcium channels since it was inhibited by the diphenylbutylpiperidine antagonist fluspirilene and by 20 mM Mg2+, and was enhanced by the dihydropyridine agonist, Bay K8644. The induction of the vesicular monoamine transporter by neuronal depolarization indicates the existence of a Ca2(+)-dependent mechanism of coregulation for this intrinsic component of monoaminergic synaptic vesicles and tyrosine hydroxylase. On the other hand, the apparent absence of dopamine-beta-hydroxylase induction is probably due to the continuous secretion of this intravesicular enzyme by the depolarized sympathetic neurons, an effect already observed in trans-synaptically stimulated adult sympathetic ganglion and adrenal medulla.
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PMID:Induction of the vesicular monoamine transporter by elevated potassium concentration in cultures of rat sympathetic neurons. 233 84

Ca2+-dependent protein phosphorylation has been detected in numerous tissues and may mediate some of the effects of hormones and other extracellular stimuli on cell function. In this paper we demonstrate that a Ca2+/calmodulin-dependent protein kinase similar to the enzyme previously purified and characterized from rat brain is present in PC12, a rat pheochromocytoma cell line. We show that Ca2+ influx elicited by various forms of cell stimulation leads to increased 32P incorporation into tyrosine hydroxylase (TH), a major phosphoprotein in these cells. Several other unidentified proteins are either phosphorylated or dephosphorylated as a result of Ca2+ influx. Acetylcholine stimulates TH phosphorylation by activation of nicotinic receptors. K+-induced depolarization stimulates TH phosphorylation in a Ca2+-dependent manner, presumably by opening voltage-dependent Ca2+ channels. Ca2+ influx that results from the direct effects of the ionophore A23187 also leads to TH phosphorylation. Phosphorylation of TH is accompanied by an activation of the enzyme. These Ca2+-dependent effects are independent of cyclic AMP and thus implicate a Ca2+-dependent protein kinase as a mediator of both hormonal and electrical stimulation of PC12 cells.
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PMID:Ca2+-dependent phosphorylation of tyrosine hydroxylase in PC12 cells. 241 38

High levels of calcium, as well as calcium ionophores, have been reported to inhibit the anterograde transport of proteins. The effect of the calcium ionophore, A23187, on the retrograde axonal transport of proteins was therefore investigated. The uptake of antibodies to dopamine-beta-hydroxylase (anti-D beta H) by sympathetic nerve terminals in the iris and their subsequent accumulation in the superior cervical ganglion was inhibited by up to 65% by A23187 (6 nmol, i.o.). At this dose, catecholamine fluorescence in the iris was reduced, indicating a high rate of exocytosis, but tyrosine hydroxylase levels and the capacity of the treated irides to take up noradrenaline were unaffected. Higher amounts of A23187 (28 nmol, i.o.) did not cause a greater degree of inhibition of retrograde transport. However, this dose was toxic to the neurons, as shown by a 68% decrease in the ability of the nerve terminals in the iris to take up [3H]noradrenaline. This loss of function occurred gradually over a 12-h period. On the other hand, tyrosine hydroxylase levels were unaffected by 28 nmol A23187. The toxicity of A23187 may be a consequence of a build up in intracellular calcium, but such toxicity did not lead to any apparent loss of nerve terminals within a 3-day period.
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PMID:Inhibition of the retrograde axonal transport of dopamine-beta-hydroxylase antibodies by the calcium ionophore A23187. 241 13

Mechanisms regulating peptidergic, noradrenergic and cholinergic development were compared in dissociated cell cultures of neonatal rat sympathetic ganglia. The majority of cultured neurons contained at least two neurotransmitters and many neurons contained three or more. These studies were undertaken to determine whether co-existing transmitters were co-ordinately regulated by the environment. Co-culture of sympathetic neurons with ganglion non-neuronal cells increased substance P and choline acetyltransferase activity but decreased somatostatin and tyrosine hydroxylase activity. Conversely, elimination of non-neuronal cells virtually abolished neuronal expression of substance P and choline acetyltransferase and increased somatostatin and tyrosine hydroxylase. Consequently, under these conditions, somatostatin and tyrosine hydroxylase were similarly regulated, whereas substance P was associated with choline acetyltransferase. By contrast, stimulation of adenylate cyclase or treatment with membrane-permeable adenosine 3',5'-phosphate analogs increased tyrosine hydroxylase and decreased choline acetyltransferase, but had no effect on substance P or somatostatin levels. Moreover, potassium- or veratridine-induced membrane depolarization increased tyrosine hydroxylase but decreased substance P, somatostatin and norepinephrine levels. However, inhibition of neurotransmitter release with magnesium or calcium-free medium prevented the decrease in norepinephrine levels but not the decrease in substance P and somatostatin. Consequently, the effects of membrane depolarization on peptide levels cannot be ascribed to release and subsequent depletion of substance P and somatostatin and must result from decreased net synthesis (synthesis minus catabolism) of the transmitters. Nerve growth-factor treatment also differentially regulated transmitter metabolism; nerve growth factor increased protein-specific activities of tyrosine hydroxylase and choline acetyltransferase but did not increase the protein-specific content of substance P and somatostatin. Quantitative transmitter expression was also influenced by neuron density; increasing density elevated substance P and choline acetyltransferase activity but decreased somatostatin and tyrosine hydroxylase activity per neuron. Finally, culture of sympathetic neurons in a defined (serum-free) medium also altered some but not all traits, decreasing substance P, somatostatin and choline acetyltransferase without any change in tyrosine hydroxylase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential regulation of peptide and catecholamine characters in cultured sympathetic neurons. 241 73

Mouse neuroblastoma X embryonic Chinese hamster brain explant hybrid cell line (NCB-20) forms functional synapses when intracellular cyclic AMP levels are elevated for a prolonged period of time. NCB-20 cells were labeled with [32P]orthophosphate under conditions where 2-chloroadenosine gave maximum increases of 32P incorporation into tyrosine hydroxylase in nerve growth factor dibutyryl cyclic AMP-differentiated PC12 (pheochromocytoma) cells. When NCB-20 cells were exposed to activators [5-hydroxytryptamine (5-HT), prostaglandin E1, or forskolin], resulting in activation of cyclic AMP-dependent protein kinase, increased 32P incorporation into two major proteins [130 kilodaltons (kDa) and 90 kDa] occurred. 5-HT (in the presence of phosphodiesterase inhibitor, isobutylmethylxanthine) gave a three- to fourfold increase, and forskolin a four- to sevenfold increase in 32P incorporation into the 90-kDa protein. [D-Ala2,D-Leu5]-enkephalin, which decreased cyclic AMP levels and reversed the 2-chloroadenosine-stimulated phosphorylation of tyrosine hydroxylase in differentiated PC12 cells, also reversed the stimulation of phosphorylation of the 90-kDa protein in NCB-20 cells. Pretreatment of NCB-20 cells with a calcium ionophore, A23187, gave increased phosphorylation of the 90- and 130-kDa proteins, but phorbol esters such as 12-O-tetradecanoylphorbol 13-acetate (tumor promoting agent), cell depolarization with high K+, or pretreatment with dibutyryl cyclic GMP had no effect on phosphorylation of these proteins. In contrast, phosphorylation of an 80-kDa protein was decreased by forskolin, but increased following activation of the calcium/phospholipid-dependent kinase with tumor promoting agent. Neither the 90-kDa nor the 80-kDa protein showed any immunological cross-reactivity with synapsin, a major synaptic protein known to be phosphorylated by cyclic AMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase, but not calcium/phospholipid-dependent protein kinase. This suggests that in NCB-20 cells, several unique proteins can be phosphorylated by cyclic AMP-dependent protein kinase in response to hormonal elevation of cyclic AMP levels. In contrast, an 80-kDa protein is the primary substrate for calcium/phospholipid-dependent protein kinase, and its phosphorylation is inhibited by agents that elevate cyclic AMP levels and thereby activate cyclic AMP-dependent protein kinase.
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PMID:Neuromodulator-mediated phosphorylation of specific proteins in a neurotumor hybrid cell line (NCB-20). 245 Jan 74

Under phosphorylating conditions, addition of Ca2+ or cyclic AMP to the 100,000 g supernatant of purified bovine adrenal chromaffin cells increases both the incorporation of 32P into tyrosine hydroxylase and the activity of the enzyme. Combining maximally effective concentrations of each of these stimulating agents produces an additive increase in both the level of 32P incorporation into tyrosine hydroxylase and the degree of activation of the enzyme. The increased phosphorylation by Ca2+ is due to stimulation of endogenous Ca2+-dependent protein kinase activity and not inhibition of phosphoprotein phosphatases. When the chromaffin cell supernatant is subjected to diethylaminoethyl (DEAE) chromatography to remove calmodulin and phospholipids, tyrosine hydroxylase is no longer phosphorylated or activated by Ca2+; on the other hand, phosphorylation and activation of tyrosine hydroxylase by cyclic AMP are not affected. Subsequent replacement of either Ca2+ plus calmodulin or Ca2+ plus phosphatidylserine to the DEAE-fractionated cell supernatant restores the phosphorylation, but not activation of the enzyme. Reverse-phase HPLC peptide mapping of tryptic digests of tyrosine hydroxylase from the 100,000 g supernatant shows that the Ca2+-dependent phosphorylation occurs on three phosphopeptides, whereas the cyclic AMP-dependent phosphorylation occurs on one of these peptides. In the DEAE preparation, either cyclic AMP alone or Ca2+ in the presence of phosphatidylserine stimulates the phosphorylation of only a single phosphopeptide peak, the same peptide phosphorylated by cyclic AMP in the crude supernatant. In contrast, Ca2+ in the presence of calmodulin stimulates the phosphorylation of three peptides having reverse-phase HPLC retention times that are identical to peptides phosphorylated by Ca2+ addition to the crude unfractionated 100,000 g supernatant. Rechromatography of the peaks from each of the in vitro phosphorylations, either in combination with each other or in combination with each of the seven peaks generated from phosphorylation of tyrosine hydroxylase in situ, established that cyclic AMP, Ca2+/phosphatidylserine, and Ca2+/calmodulin all stimulate the phosphorylation of the same reverse-phase HPLC peptide: in situ peptide 6. Ca2+/calmodulin stimulates the phosphorylation of in situ peptides 3 and 5 as well. Thus, tyrosine hydroxylase can be phosphorylated in vitro by protein kinases endogenous to the chromaffin cell. Phosphorylation occurs on a maximum of three of the seven in situ phosphorylated sites, and all three of these sites can be phosphorylated by a Ca2+/calmodulin-dependent protein kinase.
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PMID:In vitro phosphorylation of bovine adrenal chromaffin cell tyrosine hydroxylase by endogenous protein kinases. 256 9

Secretin and vasoactive intestinal peptide (VIP) are known to stimulate tyrosine hydroxylase (TH) activity acutely in the rat superior cervical ganglion (SCG). Because TH-containing neurons in the SCG innervate the iris, submaxillary gland, and pineal gland, we examined the effects of secretin and VIP in these 3 autonomic end organs in vitro. Both peptides stimulated TH activity in each tissue. These stimulations resembled those in the SCG in that (1) secretin displayed a higher potency than VIP in all 3 end organs, (2) the peptide effects were unchanged when calcium was excluded from the incubation medium, and (3) they were mimicked by activators of the cyclic adenosine monophosphate (cAMP) pathway. These findings indicate that secretin and VIP can regulate transmitter metabolism in both the cell bodies and axon terminals of neurons originating in the SCG. Furthermore, the data raise the possibility that catecholamine synthesis in sympathetic nerve terminals is modulated by peptides released by other, nearby nerve endings.
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PMID:Secretin and vasoactive intestinal peptide activate tyrosine hydroxylase in sympathetic nerve endings. 256 76


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