Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A significant activation of tryptophan hydroxylase (TPH) was achieved by the addition of 1 mM ATP and 10 mM MgCl2 to 100,000g supernatant prepared from mouse midbrain. The activation produced an increase of enzyme activity by 50-70% above control. Cyclic AMP was not a necessary component in the activation as initially suspected; neither was the involvement of a cyclic AMP-dependent protein kinase detected. The enzyme activation by Mg+2-ATP was totally retained after dialysis, thus excluding the possibility of an allosteric effect. In contrast to the activation, TPH was found to be sensitive to inactivation by acid phosphatase, a dephosphorylating enzyme. These findings are consistent with the proposal that the enzyme activation may involve a phosphorylation process. Furthermore, the activation by Mg+2-ATP in the brain preparations was only minimally observed from neonatal mice and could be abolished from adult mice by administration of hydrocortisone. It appears that the phosphorylation process, as postulated here, may be under developmental and hormonal influences.
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PMID:Activation of brain tryptophan hydroxylase by a phosphorylating system. 21 15

Tryptophan hydroxylase in the rat pineal gland undergoes diurnal rhythmic activity. Rat pineal glands exhibit increased tryptophan hydroxylase activity when incubated with a cyclic AMP analogue in vitro. Cyclic AMP-dependent protein kinase phosphorylates tryptophan hydroxylase, purified from rat brain, without any modification of its enzyme activity under our experimental conditions. Actinomycin D or cycloheximide decreases the stimulating effect of the cyclic AMP analogue on pineal tryptophan hydroxylase activity. Incubation of pineal glands in the presence of [35S]methionine showed a cyclic AMP-induced increase in tryptophan hydroxylase synthesis. These results explain the circadian rhythm of tryptophan hydroxylase activity in the rat pineal gland and suggest that the regulation of tryptophan hydroxylase expression by cyclic AMP occurs probably either at the translational level or via transient expression of a transcriptional regulatory element.
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PMID:Tryptophan hydroxylase synthesis is induced by 3',5'-cyclic adenosine monophosphate during circadian rhythm in the rat pineal gland. 165 76

Tyrosine and tryptophan hydroxylases are the key enzymes in the regulation of catecholamine and serotonin levels in neurons and other endocrine cells. Among the mechanisms proposed for the modulation of activity, phosphorylation of the enzyme is believed to be of functional significance with respect to the stimulus-response coupling, but the precise mechanism is unknown. Here, we show the existence of multiple, distinct forms of the 14-3-3 activator protein, a neuronal protein essential for activation of tyrosine and tryptophan hydroxylases by Ca2+/calmodulin-dependent protein kinase type II. Bovine brain 14-3-3 protein was resolved by reversed-phase chromatography into seven polypeptides (alpha to eta), all of which were active towards tryptophan hydroxylase when the renatured preparations were assayed in the presence of Ca2+, calmodulin and the protein kinase. Determination of the amino acid sequences of the beta and gamma chains and comparison of the sequences with the previously determined sequence of the eta chain revealed that these molecules are highly homologous, and share a common structural feature in containing an extremely acidic C-terminal region predicted as a domain for interaction with the phosphorylated hydroxylases. Northern blot analysis indicated that the beta, gamma and eta chain are expressed abundantly in the brain; however, these polypeptides appear to be expressed with different tissue specificities because gamma mRNA is found only in the brain, while lower levels of beta and eta mRNAs are detected in several other tissues. These findings suggest the involvement of a diverse family of the activator protein in the stimulus-coupled, Ca2(+)-dependent regulation of monoamine biosynthesis.
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PMID:Distinct forms of the protein kinase-dependent activator of tyrosine and tryptophan hydroxylases. 167 Nov 2

The tryptophan hydroxylase activity of the crude extract from rat brain stem was stimulated approximately 2-fold by incubation with cAMP analogues under protein phosphorylating conditions. The cAMP-dependent activation process of the enzyme needed not only cAMP-dependent protein kinase but also activator protein. The kinetic properties of the enzyme activated by cAMP-dependent protein kinase were very similar to those of the enzyme activated by calmodulin-dependent protein kinase II.
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PMID:Involvement of activator protein in the activation of tryptophan hydroxylase by cAMP-dependent protein kinase. 216 81

Tryptophan hydroxylase is activated in a crude extract by addition of ATP and Mg2+. This activation is reversible and requires in addition both Ca2+ and calmodulin. Thus, phosphorylation by an endogenous calmodulin-dependent protein kinase has long been suspected. Now that we have prepared a specific polyclonal antibody to rat brain tryptophan hydroxylase, we have been able to prove that this hypothesis is correct. After incubation of purified tryptophan hydroxylase with Ca2+/calmodulin-dependent protein kinase together with [gamma-32P]ATP, Mg2+, Ca2+, and calmodulin, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and blotting of the enzymes onto nitrocellulose sheets, we could label the band of tryptophan hydroxylase by the antiserum and the peroxidase technique and show by autoradiography that 32P was incorporated into this band. By measuring the radioactivity, we calculated that about 1 mol of phosphate was incorporated per 8 mol of subunits of the enzyme (2 mol of native enzyme). Because the concentration of ATP which we employed (50 microM) gives about half-maximal activation in crude extract compared to saturating ATP conditions (about 1 mM), this result indicates that the incorporation of at least 1 mol of phosphate/mol of tetramer of native tryptophan hydroxylase is required for maximal activation.
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PMID:Formal demonstration of the phosphorylation of rat brain tryptophan hydroxylase by Ca2+/calmodulin-dependent protein kinase. 254 52

Evidence is presented indicating that a cAMP-dependent mechanism activates tryptophan hydroxylase (TrpH), the rate-limiting enzyme for serotonin (5-HT) biosynthesis. Forskolin, a selective activator of adenylate cyclase, stimulated 5-HT formation in synaptoneurosome preparations of rat striatum, substantia nigra, hypothalamus, and amygdala. Further studies of striatum revealed that the forskolin-induced activation of serotonin synthesis is readily reversible. Also, it may be self-limited by a mechanism of desensitization, since after an initial exposure to forskolin followed by removal, a re-exposure of synaptoneurosomes to forskolin was no longer stimulatory. In contrast to these results for 5-HT synthesis, forskolin-induced stimulation of dopamine synthesis persisted following removal of forskolin; hence the response was not rapidly reversible or desensitized. In soluble extracts of striatum, 8-thiomethyl-cyclic AMP enhanced TrpH activity, supporting a direct role of cyclic AMP and cyclic AMP-dependent protein kinase in regulating TrpH. In agreement with previous reports, 8-thiomethyl cyclic AMP also stimulated tyrosine hydroxylase activity in soluble striatal extracts. We conclude that cyclic AMP is an important regulator of TrpH, in addition to its known effects on tyrosine hydroxylase.
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PMID:Regulation of tryptophan hydroxylase activity by a cyclic AMP-dependent mechanism in rat striatum. 282 48

This investigation was carried out to determine if calcium prolongation of ethanol-induced sleep is mediated by calmodulin and a calmodulin-dependent protein kinase. The duration of ethanol-induced sleeping time in ddY male mice was measured following the administration of CaCl2 (20, 40, 80 and 200 mumol/kg, intraperitoneally (IP) both with and without the calmodulin antagonists, W-7: [N-(6-Aminohexyl)-5-chloro-1-naphthalenesulfonamide] (4.2 micrograms/mouse, intraventricular (IVT) or trifluoperazine (TFP; 1.8 micrograms/mouse, IVT). When CaCl2 was administered in a dose dependent manner the duration of ethanol-induced sleep was prolonged. The prolongation was antagonized by W-7 and TFP. When mice were treated with W-7 or TFP together with serotonin (5-HT; 15 nmol/mouse, IVT), dopamine (DA; 30 nmol/mouse, IVT) or norepinephrine (NE; 30 nmol/mouse, IVT), the sleeping time induced by ethanol and calcium was enhanced. This finding suggests that W-7 and TFP selectively inhibit the synthesis of 5-HT, DA and NE, but they do not affect other neuronal functions of these biogenic amines. The results would suggest a probable mechanism in which Ca++ prolongs ethanol-induced sleeping time by activating tyrosine hydroxylase and tryptophan hydroxylase through intracerebral calmodulin and calmodulin-dependent protein kinase, which subsequently raise the levels of 5-HT, DA and NE.
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PMID:Effect of calmodulin antagonists on calcium and ethanol-induced sleeping time in mice. 407 Mar 38

The brain tryptophan hydroxylase is known to be activated by magnesium adenosine triphosphate (MgATP). This activation has been suspected to be a case of enzyme phosphorylation, although convincing evidence is still lacking. In supernatants (100,000 g) from adult mouse midbrains, the addition of 1 mM ATP and 10 mM MgCl2 could increase the tryptophan activity by 70-90%, when the enzyme activity was determined at a subsaturating concentration of 6-MPH4 (0.2 mM). The present study has revealed that the enzyme activation by MgATP could only be achieved from mice after 12 days of postnatal age. No activation was found in midbrain preparations from younger animals, although a substantial level of tryptophan hydroxylase activity was already present. The possibility that some required component(s) for the enzyme activation may be lacking during early development was tested by mixing a dialyzed adult preparation with the neonatal midbrain supernatant. Under these conditions, the tryptophan hydroxylase in the neonatal supernatant was activated by MgATP. Furthermore, the addition of a crude protein kinase fraction from adult midbrain cytosol was also capable of restoring the enzyme activatability in the neonatal preparation. It appears that the lack of activatability by MgATP alone during early development was due to absence of one or more biochemical factors required for the activation.
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PMID:Activation of midbrain tryptophan hydroxylase by MgATP. Absence during early postnatal development. 698 83

The 14-3-3 protein family plays a role in a wide variety of cell signaling processes including monoamine synthesis, exocytosis, and cell cycle regulation, but the structural requirements for the activity of this protein family are not known. We have previously shown that the 14-3-3 protein binds with and activates phosphorylated tryptophan hydroxylase (TPH, the rate-limiting enzyme in the biosynthesis of neurotransmitter serotonin) and proposed that this activity might be mediated through the COOH-terminal acidic region of the 14-3-3 molecules. In this report we demonstrate, using a series of truncation mutants of the 14-3-3 eta isoform expressed in Escherichia coli, that the COOH-terminal region, especially restricted in amino acids 171-213, binds indeed with the phosphorylated TPH. This restricted region, which we termed 14-3-3 box I, is one of the structural regions whose sequence is highly conserved beyond species, allowing that the plant 14-3-3 isoform (GF14) could also activate rat brain TPH. The 14-3-3 box I is the first functional region whose activity has directly been defined in the 14-3-3 sequence and may represent a common structural element whereby 14-3-3 interacts with other target proteins such as Raf-1 kinase. The result is consistent with the recently published crystal structure of this protein family, which suggests the importance of the negatively charged groove-like structure in the ligand binding.
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PMID:Identification of the site of interaction of the 14-3-3 protein with phosphorylated tryptophan hydroxylase. 749 62

The effect of protein kinase A on the catalytic activity and phosphorylation of brain tryptophan hydroxylase was examined. Stimulation of endogenous protein kinase A by cyclic AMP or its analogues, dibutyryl-cyclic AMP and 8-thiomethyl-cyclic AMP, failed to activate tryptophan hydroxylase. The activation of tryptophan hydroxylase by calcium/calmodulin-phosphorylating conditions was not modified by cyclic AMP. Endogenous protein kinase A phosphorylated a large number of proteins and tryptophan hydroxylase could be identified as one substrate by sucrose gradient centrifugation, immunoprecipitation, and immunoblotting. These results indicate that tryptophan hydroxylase is phosphorylated by protein kinase A in brain and question whether this protein kinase exerts direct regulatory influence over tryptophan hydroxylase activity via phosphorylation.
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PMID:Tryptophan hydroxylase is phosphorylated by protein kinase A. 761 49


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