Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Bilateral infusion of dehydroepiandrosterone (DHEA) given intracerebroventricularly blocked the sound stress-induced increase in tryptophan hydroxylase activity observed ex vivo in midbrain and cortex but had no effect on the level of tryptophan hydroxylase activity from sham-stressed rats. DHEA (20 micrograms total dose) given bilaterally into the region of the central nucleus of the amygdala, 30 min prior to 1 h sound stress, also blocked the increase in enzyme activity in a dose-dependent manner. The DHEA treatment did not alter the activation of the enzyme seen in vitro in the presence of phosphorylating conditions. The effect of DHEA was steroid specific in that other sex steroids, such as estrogen, androgens, or progesterone, were without any effect. Coadministration, 20 micrograms each, of the potent glucocorticoid agonist, RU 28362, with DHEA 30 min prior to 1 h sound stress completely blocked the DHEA suppressive effect on sound stress-induced increases in tryptophan hydroxylase activity. The results obtained suggest that DHEA blocks this increase in tryptophan hydroxylase activity by antagonizing the effects of glucocorticoid.
Mol Cell Neurosci 1994 Apr
PMID:Intracranial dehydroepiandrosterone blocks the activation of tryptophan hydroxylase in response to acute sound stress. 803 85

Arabidopsis cDNA clones of GF14 proteins originally were isolated on the basis of their association with the G-box DNA/protein complex by a monoclonal antibody screening approach. GF14 proteins are homologous to the 14-3-3 family of mammalian proteins. Here we demonstrate that recombinant GF14 omega, one member of the Arabidopsis GF14 protein family, is a dimeric protein that possesses many of the attributes of diverse mammalian 14-3-3 homologues. GF14 omega activates rat brain tryptophan hydroxylase and protein kinase C in a manner similar to the bovine 14-3-3 protein. It also activates exoenzyme S of Pseudomonas aeruginosa as does bovine brain factor activating exoenzyme S (FAS), which is itself a member of 14-3-3 proteins. In addition, GF14 omega binds calcium, as does the human 14-3-3 homologue reported to be a phospholipase A2. These results indicate that a single isoform of this plant protein family can have multiple functions and that individual GF14 isoforms may have multiple roles in mediating signal transductions in plants. However, GF14 omega does not regulate growth in an in vivo test for functional similarity to the yeast 14-3-3 homologue, BMH1. Thus, while a single plant GF14 isoform can exhibit many of the biochemical attributes of diverse mammalian 14-3-3 homologues, open questions remain regarding the physiological functions of GF14/14-3-3 proteins.
Plant Mol Biol 1994 Jul
PMID:A single Arabidopsis GF14 isoform possesses biochemical characteristics of diverse 14-3-3 homologues. 806 18

Recombinant mouse tryptophan hydroxylase (TPH) was expressed in large quantities in Escherichia coli strain MC 1061, using a bacterial expression vector, pKS, containing the full coding region of mouse TPH. Specific polyclonal antiserum to the subunit of the recombinant mouse TPH was produced in rabbit by injecting the TPH band cut from SDS-polyacrylamide slab gels. The resultant antiserum recognized a single identical protein band (MW = 54,000) from rat dorsal raphe area, pineal gland, and brain stem by Western blot analysis. The specific activity of recombinant mouse TPH obtained was equivalent to that of TPH purified from rat brain. The recombinant mouse TPH was stable for 3 days at 4 degrees C but lost 25% of the original activity for the same period at -20 degrees C. A serotonin concentration greater than 1 mM inhibited TPH activity under our assay conditions in a concentration-dependent fashion. The recombinant mouse TPH exhibited a charge isozyme corresponding to that of pineal gland TPH as applied to chromatofocusing column chromatography. Taken together, our results show that recombinant mouse TPH, expressed in large quantities in E. coli is not only enzymatically highly active but also shares many biochemical and immunochemical properties with native TPH.
Mol Cell Neurosci 1994 Feb
PMID:Characterization of recombinant mouse tryptophan hydroxylase expressed in Escherichia coli. 808 17

Repeated high doses of d-fenfluramine (dF; 10 mg/kg, i.p. twice daily for 4 days) markedly reduced serotonin (5-HT) concentrations in the hippocampus and striatum of rat brain up to 1 month after treatment, while tryptophan hydroxylase (TPH) levels were reduced only in the hippocampus 5 days after injection. Unlike dF, an intracerebroventricular (i.c.v.) injection of 5,7-dihydroxytryptamine (5,7-DHT 150 micrograms/20 microliters) induced a marked and long-lasting reduction of 5-HT and TPH in both brain regions. Thirty days after injection, 5,7-DHT, but not dF, markedly reduced the number of labelled neurons in the dorsal and ventral regions of the nucleus raphe dorsalis (NRD) and raised the levels of TPH mRNA in the spared neurons at all times examined. TPH mRNA levels were raised 5 and 15 days after dF treatment in the NDR suggesting that changes in the TPH gene expression or transcript stability result following 5-HT depletion. These data are in agreement with the suggestion that 5,7-DHT damages 5-HT nerve terminals and perikarya, but leave unanswered the question of the mechanism of the long-lasting reduction of 5-HT levels caused by high, repeated doses of dF.
Brain Res Mol Brain Res 1993 Aug
PMID:Effect of d-fenfluramine and 5,7-dihydroxytryptamine on the levels of tryptophan hydroxylase and its mRNA in rat brain. 841 72

Ciliary neurotrophic factor (CNTF) is a multifunctional cytokine that mediates survival and differentiation of neurons as well as many other cell types. In this study, CNTF and leukemia inhibitory factor (LIF) reduced the apparent number of primary serotonergic neurons in E14 raphe culture by 90% as determined by immunocytochemistry for serotonin (5HT). The reduction in 5HT cell number was not due to neuronal loss as removal of CNTF after 4 days in culture resulted in a partial restitution of the serotonergic phenotype. In the RN46A serotonergic cell line which is induced to become serotonergic by brain-derived neurotrophic factor (BDNF), the addition of CNTF suppressed tryptophan hydroxylase and 5HT synthesis and increased choline acetyl transferase (ChAT) expression by 6-fold and ChAT activity by 20- to 30-fold over 12 days. As with the primary neurons, removal and replacement of CNTF with BDNF after 4 days resulted in a partial restitution of 5HT expression. Moreover, other members of the CNTF-cytokine family that use gp130 and/or LIF receptor beta as their signal transducing receptors-LIF, oncostatin M, interleukin 6, and interleukin 11-had similar effects on increasing ChAT activity and reducing 5HT expression in RN46A cells. Analysis of 5HT levels showed no significant difference in the amount of serotonin between wild-type and CNTFR alpha knockout mice at birth, suggesting that the potential to switch phenotype mediated through CNTFR alpha is a latent property of neuroepithelial precursors in the raphe nucleus.
Mol Cell Neurosci 1996 Mar
PMID:CNTF induces raphe neuronal precursors to switch from a serotonergic to a cholinergic phenotype in vitro. 872 4

The expression of mRNAs coding for tryptophan hydroxylase (TPOH), the first enzyme involved in melatonin synthesis, has been studied in the rat adult pineal gland at four different circadian time points by in-situ hybridization using an oligonucleotide probe. TPOH mRNAs were detected at all chosen time-points. The lowest level was seen at 13:00 h. Quantification of the hybridization signals demonstrated a significant increase in expression (+16.5%) between 13:00 h and 19:30 h, with the values at 23:30 h and 09:00 h being similar to that of 19:30 h. These results coincide with the nycthemeral rhythm of TPOH activity. Day/night rhythms in the rat pineal gland are controlled by noradrenaline release at lights-off, which results in an increase in cAMP levels and in gene activation. This study suggests that the TPOH gene might be one such gene whose activation is stimulated in this way.
Brain Res Mol Brain Res 1996 Aug
PMID:Nycthemeral expression of tryptophan hydroxylase mRNAs in the rat pineal gland. 884 21

Dexfenfluramine (DF), given in high doses, can produce long-lasting decreases in brain levels of serotonin (5-HT) and 5-HT transporter (5-HTT) protein. The purpose of this study was to determine if DF-induced decreases in 5-HT and 5-HTT in rat forebrain are correlated with compensatory changes in the expression of the genes for tryptophan hydroxylase (TPH) and 5-HTT in the dorsal raphe nucleus. Gene transcripts were measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Rats were treated with either one or eight injections of DF at either high (10 mg/kg) or low (2 mg/kg) doses. A positive control group for 5-HT cell loss received a single cerebroventricular injection of 5,7-dihydroxytryptamine (DHT). Rats were killed either 5, 15 or 30 days after their last treatment. Paroxetine binding to the 5-HTT protein in frontal cortex was, as expected, reduced in all of the treated groups relative to vehicle controls. TPH mRNA levels in the dorsal raphe of animals that received DHT were significantly higher than those measured in all other treatment groups 15 days following treatment. By 30 days, the amount of TPH mRNA in DHT-treated rats had fallen to well below control levels. None of the DF regimens significantly affected TPH mRNA levels. Unlike the TPH mRNA changes in DHT-treated rats, the 5-HTT mRNA levels in the dorsal raphe declined progressively throughout the 30 day survival period. None of the DF regimens significantly affected 5-HTT mRNA levels. The significance of these data are discussed in terms of whether loss of forebrain markers for 5-HT reflects either the loss of fine caliber 5-HT axon terminals or a decrease in the expression of these markers in the somata of these cells which are located in the dorsal raphe.
Brain Res Mol Brain Res 1996 Sep 05
PMID:Effects of dexfenfluramine or 5,7-dihydroxytryptamine on tryptophan hydroxylase and serotonin transporter mRNAS in rat dorsal raphe. 888 42

We have previously shown that the level of [35S]methionine incorporation into tryptophan hydroxylase (TPH) shows a circadian rhythm in cultured chick pineal cells. The TPH protein oscillation persists in constant darkness, peaks in the early night and can be phase-shifted by light, in parallel to the effect of these treatments on melatonin synthesis. We have cloned and sequenced a full-length cDNA for chick pineal TPH. Levels of TPH mRNA show a robust diurnal oscillation both in vivo and in vitro. The rhythm in TPH mRNA also persists in constant darkness, suggesting that TPH mRNA synthesis and/or turnover is regulated by an endogenous circadian clock in cultured chick pineal cells. The circadian oscillation of TPH constitutes the first described circadian rhythm of a chick pineal gene at the mRNA level.
Brain Res Mol Brain Res 1996 Nov
PMID:Molecular cloning of chick pineal tryptophan hydroxylase and circadian oscillation of its mRNA levels. 891 76

Serotonergic neurons play key roles in modulating a wide variety of behavioral and homeostatic processes. However, there is a paucity of good model systems to study these neurons at a molecular level. In this review we will present evidence that cell lines derived from an unexpected source, thyroid parafollicular cells (PF) (also called C cells), fit the criteria for use as models for the study of serotonergic neurons. A strength of PF cell lines over other cell lines is that the parental PF cells have serotonergic properties and a neuronal potential that is consistent with their neural crest origin. Furthermore, PF cells and PF cell lines are capable of expressing the fundamental properties of serotonergic neurons, including: (1) serotonin (5-HT) biosynthesis by tryptophan hydroxylase (TPH), (2) vesicular 5-HT storage and regulated release, (3) expression of a 5-HT autoreceptor, and (4) expression of the 5-HT transporter. In this review, we will focus primarily on the serotonergic and neuronal properties of the rat CA77 PF cell line and the parental rat PF cells. The applicability of CA77 cells for molecular analyses will be described. First, their use for studies on the glucocorticoid regulation of the TPH gene will be discussed. Second, control of the calcitonin/calcitonin gene-related peptide (CT/CGRP) gene will be discussed, with particular emphasis on the application of serotonergic drugs in treating migraine headaches. These examples highlight the versatility of thyroid PF cell lines as a system for studying the control of both serotonin biosynthesis and physiological actions.
Mol Neurobiol 1996 Dec
PMID:Thyroid parafollicular cells. An accessible model for the study of serotonergic neurons. 898 73

Two models of genetically epilepsy-prone rat (GEPR) exist, the GEPR-3 and GEPR-9, GEPR-3 and GEPR-9 share a deficiency in presynaptic norepinephrine (NE) and serotonin (5HT) content in specific regions of the central nervous system (CNS). The presynaptic content of dopamine (DA) does not appear to be altered in either adult GEPR strain compared to Sprague-Dawley (SD) rats, the strain from which the GEPR was derived. Presynaptic content of monoamine neurotransmitters, such as NE, 5HT and DA, are maintained by several regulatory proteins which include: synthesis, re-uptake, release, degradation and vesicular transport. To further characterize the monoamine deficiency observed in the GEPR, the mRNA level of the rate limiting enzymes for the synthesis of NE, 5HT and DA and each of the neurotransporter proteins were measured in seizure-naive GEPR-3, GEPR-9 and SD rats. In the locus coeruleus (LC), the major noradrenergic locus, tyrosine hydroxylase (TH) mRNA level was significantly reduced only in GEPR-9 animals compared to SD rats and GEPR-3, while NE transporter (NET) mRNA was significantly elevated in GEPR-3 compared to SD rats and GEPR-9. TH and DA transporter (DAT) mRNA was measured in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), ventral tegmental area (VTA) and zona incerta (ZI), DAT mRNA level was significantly reduced in all dopaminergic neurons in the GEPR-3 compared to SD rats and GEPR-9, while TH mRNA level was significantly elevated in the SNpc/VTA equally in GEPR-3 and GEPR-9 compared to SD rats. In the ZI, TH mRNA level was significantly reduced in GEPR-3 compared to SD rats and GEPR-9. In the dorsal raphe (DR), a major serotonergic locus, tryptophan hydroxylase (TRH) mRNA level was not significantly different from SD in either strain of GEPR; however, 5HT transporter (SERT) mRNA level was significantly reduced in GEPR-9 in the dorsal and lateral regions of the DR compared in SD rats and GEPR-3. These data indicate that two of the regulatory systems that maintain NE, 5HT and DA content are altered in a differential manner in seizure-naive GEPR-3 compared to seizure-naive GEPR-9, with GEPR-3 showing more alterations in dopaminergic neurons. It is uncertain at the present time how these alterations in mRNA level relate to the enhanced seizure susceptibility of these animals. It was apparent that a straightforward correlation between neurotransmitter loss to transcriptional changes in synthesizing enzymes mRNA or to re-uptake protein mRNA was not observed in noradrenergic and serotonergic neurons. Therefore, the decrease in presynaptic NE and 5HT tissue content in these animals may be due to posttranscriptional modification. In contrast, presynaptic DA tissue content which was unaltered in both strains of GEPR, shows an alteration in TH and DAT mRNA level compared to SD rats in all dopaminergic neurons examined. This indicates a possible involvement of DA in regulating the seizure susceptibility of these animals.
Brain Res Mol Brain Res 1996 Dec 31
PMID:Alterations in mRNA expression of systems that regulate neurotransmitter synaptic content in seizure-naive genetically epilepsy-prone rat (GEPR): transporter proteins and rate-limiting synthesizing enzymes for norepinephrine, dopamine and serotonin. 903 38


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