Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The involvement of abdominal afferent vagal activity and serotonergic mechanisms were examined following intravenous administration of talipexole, a dopamine D2 receptor agonist used for treatment of Parkinson's disease, in anesthetized rats. Intravenous administration of dopamine receptor agonists including D1/D2 components increased the spontaneous firing of afferent vagal neurons as did 2-methyl-5-hydroxytryptamine. Both talipexole (0.25-1.0 mg/kg) and bromocriptine (1.0-10.0 mg/kg) increased vagal nerve activity in a dose-dependent manner, and the effect of 10 mg/kg of bromocriptine was significantly greater than that noted with 1.0 mg/kg of talipexole. Increasing vagal firing induced by talipexole was prevented by pretreatment with granisetron, but not with metoclopramide or by spinal section, indicating that afferent vagal firing was mediated via stimulation of the 5-HT3 receptors on the neurons and secondarily caused by stimulation of dopamine receptors. On the other hand, bromocriptine at 5 mg/kg increased 5-HIAA concentration in the ileum, and serotonin turnover (5-HIAA/5-HT) was increased approximately 4-fold when compared to the vehicle group. Bromocriptine also increased the activities of tryptophan hydroxylase and monoamine oxidase. Talipexole at 0.5 mg/kg did not affect ileal 5-HT metabolism and the enzymatic activities. These findings suggest that dopamine receptor agonists may induce changes in abdominal afferent vagal activity and ileal 5-HT metabolism similar to those observed with emetic compounds, and that talipexole has a much smaller influence on serotonin-mediated responses than does bromocriptine with equipotent antiparkinsonian doses. One of the possible reason why talipexole showed fewer emetic side effects in patients with Parkinson's disease may be that the emetic responses triggered by D2 receptor stimulation may secondarily cause an increase of abdominal afferent vagal activity, which may be weakened by the 5-HT3 receptor antagonistic property of talipexole.
Res Commun Mol Pathol Pharmacol 1997 Jan
PMID:Effects of talipexole on emesis-related changes in abdominal afferent vagal activity and ileal serotonin metabolism in rats. 905 50

A human tryptophan hydroxylase intron seven polymorphism previously associated with low CSF 5-HIAA and suicidal behavior was sequenced and characterized for its potential role in TPH pre-mRNA splicing. Two polymorphic sites were identified: A218C and A779C. The 779A allelic frequency in various populations ranged from 0.43 to 0.61 and was in strong linkage disequilibrium with the A218C site. A218C provides a site for restriction fragment length polymorphism analysis. TPH mRNA was reverse-transcribed and sequenced. No aberrant splice products from the 779A or 779G TPH genes were detected nor were any other polymorphic nucleotides found.
Brain Res Mol Brain Res 1997 Apr
PMID:Sequence, splice site and population frequency distribution analyses of the polymorphic human tryptophan hydroxylase intron 7. 910 82

The effects of valproate on CNS concentrations of gamma-aminobutyric acid (GABA), glulamate (GLU), glutamine (GLN); dopamine (DA), serotonin (5-HT), and metabolites were examined in tissue extracts of caudate nucleus of genetic substrains of Balb/c mice susceptible (EP) or resistant (ER) to audiogenic seizures. Generalized tonic-clonic seizures observed in EP mice were inhibited by valproate, administered 1 h prior to testing, in a dose-response fashion. Concentrations of GABA, GLU, and GLN, which were lower in EP mice than in ER mice, were significantly increased by valproate at doses of 180 and 360 mg/kg. Concentrations of homovanillic acid (HVA) and hydroxyindoleacetic acid (5-HIAA), metabolites of DA and 5-HT, were substantially increased by valproate at these doses. The in situ activity of tyrosine hydroxylase (TH) was not significantly influenced by valproate, whereas a valproate-induced increase in tryptophan hydroxylase (TPH) activity was observed in both striatum and in midbrain tegmentum. The data are consistent with the interpretation that anti-convulsive doses of valproate influences the intraneuronal metabolism of monoamines, GABA, and glutamate concurrently. Valproate's influence on the metabolism of both major inhibitory (GABA) and excitatory (GLY amino acids in striatum could contribute to its anti-convulsive effects in genetically seizure prone mice, as well as to the accumulation of DA and 5-HT metabolites.
Mol Chem Neuropathol 1996 Apr
PMID:Effects of valproate on amino acid and monoamine concentrations in striatum of audiogenic seizure-prone Balb/c mice. 914 15

Tryptophan hydroxylase (EC 1.14, 16.4) was purified from yellowfin tuna liver and properties of this enzyme were compared with those of tryptophan hydroxylase from some other species (mouse mastocytoma and rat brain-stem). The molecular weight of the yellowfin tuna enzyme was estimated to be about 280,000 Da. This value is similar to that for the enzymes from mouse mastocytoma and rat brain-stem. On SDS-polyacrylamide gel electrophoresis analysis, yellowfin tuna enzyme was estimated to be about 96,000 Da. This value is different from that for the enzymes from mouse mastocytoma (53,000 Da) and rat brain-stem (59,000 Da) and suggests that yellowfin tuna enzyme may be a dimer of identical subunits of Mr 96,000 Da.
Comp Biochem Physiol B Biochem Mol Biol 1997 Feb
PMID:Characterization of yellowfin tuna (Thunnus albacares, Scombroidei) tryptophan hydroxylase. 915 79

A potential long-term target of glucocorticoid modulation of serotonin (5-HT) production is tryptophan hydroxylase (TPH) gene expression. However, studies on TPH gene expression have been hampered by the extremely low levels of TPH mRNA in the brain, and there have been contradictory reports on the effects of glucocorticoids on 5-HT levels. To overcome these obstacles, we have developed a sensitive competitive RT-PCR assay to directly measure TPH mRNA levels from the rat brain. We observed a tissue-specific modulation of TPH mRNA levels in the melatonin producing pineal gland and the serotonin producing raphe nuclei of the brain. Following chronic treatment of adrenalectomized rats with the synthetic glucocorticoid dexamethasone for 1 week, there was a 16-fold increase in TPH mRNA in the pineal gland that was contrasted by a decrease in TPH mRNA to 16% of the control levels in the brain. To address the mechanism of dexamethasone repression of TPH mRNA levels, we then tested a serotonergic neuronal-like cell line derived from rat thyroid C cells. Dexamethasone caused a rapid decrease in TPH mRNA levels to approximately 20% of control values in CA77 C cells. This was measured by both competitive RT-PCR and a standard hybridization assay, which confirmed the validity of the RT-PCR assay. Furthermore, the reduction of TPH mRNA levels was associated with a decrease in 5-HT levels in the CA77 C cells. Hence, glucocorticoids may alter serotonin and melatonin biosynthetic capacity by cell-specific modulation of the TPH gene.
Brain Res Mol Brain Res 1997 Sep
PMID:Tissue-specific glucocorticoid regulation of tryptophan hydroxylase mRNA levels. 933 32

The neurotransmitter biosynthetic enzymes, tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH) are each composed of an amino-terminal regulatory domain and a carboxyl-terminal catalytic domain. A chimeric hydroxylase was generated by coupling the regulatory domain of TH (TH-R) to the catalytic domain of TPH (TPH-C) and expressing the recombinant enzyme in bacteria. The chimeric junction was created at proline 165 in TH and proline 106 in TPH because this residue is within a conserved five amino-acid span (ValProTrpPhePro) that defines the beginning of the highly homologous catalytic domains of TH and TPH. Radioenzymatic activity assays demonstrated that the TH-R/TPH-C chimera hydroxylates tryptophan, but not tyrosine. Therefore, the regulatory domain does not confer substrate specificity. Although the TH-R/TPH-C enzyme did serve as a substrate for protein kinase (PKA), activation was not observed following phosphorylation. Phosphorylation studies in combination with kinetic data provided evidence that TH-R does not exert a dominant influence on TPH-C. Stability assays revealed that, whereas TH exhibited a t1/2 of 84 min at 37 degrees C, TPH was much less stable (t1/2 = 28.3 min). The stability profile of TH-R/TPH-C, however, was superimposable on that of TH. Removal of the regulatory domain (a deletion of 165 amino acids from the N-terminus) of TH rendered the catalytic domain highly unstable, as demonstrated by a t1/2 of 14 min. The authors conclude that the regulatory domain of TH functions as a stabilizer of enzyme activity. As a corollary, the well-characterized instability of TPH may be attributed to the inability of its regulatory domain to stabilize the catalytic domain.
J Mol Neurosci 1997 Aug
PMID:A chimeric tyrosine/tryptophan hydroxylase. The tyrosine hydroxylase regulatory domain serves to stabilize enzyme activity. 935 25

Besides the classical endocrine renin-angiotensin system (RAS), a local RAS has been described also in the brain. We attempted to clarify the existence of a local RAS in the pineal gland. Through the use of a ribonuclease protection assay, it proved possible to detect the mRNA for angiotensinogen (AOGEN), for the angiotensin receptor type 1A (AT1a) and 1B (AT1b) and for the angiotensin-converting enzyme (ACE) in pineal glands from rats. Renin mRNA, however, could not be found by this method. By in situ hybridization and immunocytochemistry, AOGEN mRNA was co-localized with the astrocyte marker glial fibrillary acidic protein. AT1b mRNA expression exceeded the expression of AT1a mRNA and was co-localized with the pinealocyte-specific tryptophan hydroxylase. Thus, in the mammalian pineal gland there is a local formation of the components of the RAS. The presence of angiotensin II receptors further substantiates a role for angiotensins and the pineal RAS in the physiology of this gland.
Brain Res Mol Brain Res 1998 Mar 01
PMID:Local renin-angiotensin system in the pineal gland. 955 34

Tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) both contain a C-terminal tetramerization domain composed of a leucine heptad repeat embedded within a 4,3-hydrophobic repeat. Previous mutagenesis experiments and X-ray crystallographic studies have demonstrated that these repeats are required for tetramer assembly of the hydroxylase enzymes via coiled-coil interactions. The specificity of these particular C-terminal intersubunit binding motifs was investigated by determining if TH and TPH can form heterotetramers when coexpressed in bacteria. Bacterial cells were contransformed with TH and TPH expression plasmids under kanamycin and ampicillin selection, respectively. Immunoprecipitation of induced bacterial supernatants with a TPH monoclonal antibody demonstrated that, unlike the human TH isoforms, TH and TPH do not form heterotetramers. The data suggest that specificity of oligomerization of the aromatic amino acid hydroxylases may be partially determined by polar amino acids interspersed within the coiled-coil. This finding should be influential in the development of eukaryotic expression systems and ultimately in gene therapy approaches.
J Mol Neurosci 1998 Feb
PMID:Tyrosine hydroxylase and tryptophan hydroxylase do not form heterotetramers. 958 69

Tryptophan hydroxylase (TPH) is the rate limiting enzyme in serotonin biosynthesis [D.G. Grahame-Smith, Tryptophan hydroxylation in brain, Biochem. Biophys. Res. Commun. 16 (1964) 586-592 [19]]. As such, the TPH gene is a likely target for modulation of serotonergic function, which has been associated with several psychiatric disorders [E.C. Azmitia, P.M. Whitaker-Azmitia, Awakening the sleeping giant: anatomy and plasticity of the brain serotonergic system, J. Clin. Psychiatry 52 (12, Suppl.) (1991) 4-16 [1]; R.P. Hart, R. Yang, L.A. Riley., T.L. Green, Post-transcriptional control of tryptophan hydroxylase gene expression in rat brain stem and pineal gland, Mol. Cell. Neurosci. 2 (1991) 71-77 [20]; M.J. Owens, C.B. Numeroff, Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter, Clin. Chem. 40 (1994) 288-295 [24]]. Unfortunately, it has been technically difficult to measure TPH mRNA levels in central serotonergic neurons due to its low levels. For example, detection with ribonuclease protection assays requires pooling of 5-10 dissected brainstems [M.C. Darmon, B. Guibert, V. Leviel, M. Ehret, M. Maitre, J. Mallet, Sequence of two mRNAs encoding active rat tryptophan hydroxylase, J. Neurochem. 51 (1988) 312-316 [15]; B.L. Jacobs, E.C. Azmitia, Structure and function of the brain serotonin system, Physiol. Rev. 72 (1992) 165-229 [21]]. This protocol describes the use of competitive RT-PCR to measure TPH mRNA levels from rat brain. First described in 1988, competitive RT-PCR has become an accepted method of measuring RNA abundance [M. Clementi, S. Menzo, P. Bagnarelli, A. Manzin, A. Valenza, P.E. Varaldo, Quantitative PCR and RT-PCR in virology, PCR Methods Appl. 2 (1994) 191-196 [12]; N.C.P. Cross, Quantitative PCR techniques and applications, Br. J. Haematol. 89 (1995) 693-697 [14]; K.P. Foley, M.W. Leonard, J.D. Engel, Quantitation of RNA using the polymerase chain reaction, Trends Genet. 9 (1993) 380-385 [17]; P.D. Siebert, J.W. Larrick, Competitive PCR, Nature 359 (1992) 558 [27]]. Competitive RT-PCR uses co-amplification with a known quantity of an in vitro transcribed RNA which amplifies using the same primers and thus competes for reactants with the product of interest. As the two products amplify with the same efficiency, the relative abundance of the two amplification products remains constant, and thus can be used to determine initial tissue TPH mRNA levels [G. Gilliland, S. Perrin, K. Blanchard, H.F. Bunn, Analysis of cytokine mRNA and DNA: detection and quantitation by competitive polymerase chain reaction, Proc. Natl. Acad. Sci. U.S.A. 87 (1990) 2725-2729 [18]; A.M. Wang, M. V. Doyle, D.F. Mark, Quantitation of mRNA by the polymerase chain reaction, Proc. Natl. Acad. Sci. U.S.A. 86 (1989) 9717-9721 [31]]. We first demonstrate equivalent results between RNA slot blots and competitive RT-PCR using the CA77 thyroid C cell line [M.S. Clark, A. F. Russo, Tissue-specific glucocorticoid regulation of tryptophan hydroxylase mRNA levels, Mol. Brain Res. 48 (1997) 346-354 [9]]. We then describe the use of competitive RT-PCR to measure TPH mRNA levels in RNA isolated from rat brain poly-A+ RNA.
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PMID:Measurement of tryptophan hydroxylase mRNA levels by competitive RT-PCR. 963 Jun 72

The human tryptophan hydroxylase gene (hTPH) encodes the rate-limiting enzyme in the biosynthesis of serotonin, a neurotransmitter which has been implicated in a number of psychiatric illnesses. This enzyme is expressed in a tissue-specific manner. We examined the transcriptional activity of a series of 5' deletion promoter-reporter constructs extending from nucleotide (nt) -1954 to +40 and found that the region between nt -163 and +40 contains a regulatory element important for efficient transcription of the gene, DNase I footprint analyses, using P815-HTR and HeLa nuclear protein extracts, revealed a single prominent footprint between nt -78 and -44. A cis-acting element in the footprint region was identified as an inverted CCAAT box (-67 ATTGG -63) by gel shift assays. Two base pair (bp) mutations in the core CCAAT sequence eliminated protein binding in gel shift assays and reduced transcriptional activity approximately 50% in transient transfection assays. Competitive gel shift assays showed that the protein binding to the hTPH CCAAT box was effectively competed by an oligonucleotide (oligo) harboring a binding site for CCAAT box binding factor (CBF)/nuclear factor-Y (NF-Y). A selective antibody against the B subunit of CBF/NF-Y supershifted the protein-DNA complex formed between the -90/-50 oligo probe and nuclear protein extracts. Our results indicate that the binding of CBF/NF-Y to the inverted CCAAT box is responsible for transcriptional activation of the nTPH gene.
Brain Res Mol Brain Res 1998 Mar 30
PMID:CBF/NF-Y activates transcription of the human tryptophan hydroxylase gene through an inverted CCAAT box. 964 61


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