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)

An investigation was carried out regarding the mechanism of behavioral changes in mice elicited by cold stress. Cold stress was induced in adult male mice by restraining them from free action for 2 h at 4 degrees C. As the control test, mice were restrained from free action for 2 h at room temperature. The locomotor counts in cold-stressed mice were found to be lower than in controls. The counts in cold-stressed mice were increased by IP pretreatment with EDTA or alpha-methyltyrosine (tyrosine hydroxylase inhibitor), and were further decreased by IP pretreatment with CaCl2. On the other hand, serum calcium and brain calcium levels in cold-stressed mice were increased 15-30 min and 30 min, respectively, after restraint under cold temperatures, and returned to original levels 1 h after restraint. Also, the biochemical and immunohistochemical brain dopamine levels in cold-stressed mice were higher than in control mice. The increment of brain dopamine levels in the control mice was also observed by the administration of CaCl2. Furthermore, the ability of cold stress to enhance the dopamine level in mice brains was attenuated by IP pretreatment with alpha-methyltyrosine. In light of previous reports that central calcium activates catecholamine-synthesizing enzymes via a calmodulin-dependent system, it is suggested that cold stress enhances the brain calcium level, and then increased calcium enhances dopamine synthesis in the brain through a central calcium-dependent catecholamine synthesizing system. Subsequently, increased dopamine induces behavioral changes.
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PMID:Behavioral changes in cold-stressed mice related to a central calcium-dependent-catecholamine synthesizing system. 180 45

The effect of pseudorabies virus on neuronal functions was investigated in PC12 cells. During the period investigated, choline acetyltransferase was not affected, while the acetylcholinesterase activity declined steadily starting at 12 h post infection (p.i.), reaching its minimal level of 40% of the control value at 24 h p.i. In contrast, the activity of tyrosine hydroxylase, the key enzyme in catecholamine synthesis, increased to 150% of the control level by 15 h p.i., dropping off slowly with the appearance of viral cytopathology. In parallel, the infection induced, by a process independent of the extracellular Ca2+, an increased release of dopamine at 11 h p.i., followed by noradrenaline at 20 h p.i. In the infected cells, the intracellular content of catecholamine was maintained only in the presence of a high amount of catecholamine precursors in the culture medium. Three plaque-forming units per cell was the minimal multiplicity of infection required to obtain the maximal changes in enzyme activities; higher multiplicities induced more rapidly the maximal effects on tyrosine hydroxylase and acetylcholinesterase. Inhibition of DNA synthesis did not prevent the increase in tyrosine hydroxylase activity; however, protein synthesis was required. In conclusion, infection of the PC12 cells with pseudorabies virus induced significant changes in catecholaminergic and cholinergic metabolism, indicating the ability of this virus to interfere selectively with specialized neuronal functions.
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PMID:Effects of pseudorabies virus on the neuronal properties of PC12 cells. 184 87

Tyrosine hydroxylase is activated and phosphorylated following treatment of PC-12 cells with bradykinin. In order to determine the mechanisms by which this occurs, we have evaluated the second messenger systems that may be responsible for this activation and phosphorylation. Inositol phosphates appear to play an important role in the activation and phosphorylation of tyrosine hydroxylase because bradykinin treatment significantly increased the formation of [3H]inositol phosphates and the concentration of intracellular free calcium ([Ca2+]i) in PC-12 cells. The uptake of extracellular 45Ca2+ into PC-12 cells at 1 min was significantly increased (107%) by bradykinin treatment and this increase was blocked by La3+, an inorganic calcium channel inhibitor, but not by nifedipine, an inhibitor of voltage-dependent calcium channels. The activation of tyrosine hydroxylase in PC-12 cells following bradykinin treatment was partially inhibited by La3+. Additivity experiments were performed to evaluate whether the activation and phosphorylation of tyrosine hydroxylase in PC-12 cells following treatment with bradykinin (10 microM) was similar to the activation and phosphorylation of tyrosine hydroxylase in PC-12 cells following treatment with dibutyryl cAMP (2 mM), 4 beta-phorbol-12 beta-myristate-13 alpha-acetate (PMA) (2 microM), and high K+ (56 mM). The combination of bradykinin and PMA produced additive effects, indicating that the activation of tyrosine hydroxylase by treatment with these two compounds was through different mechanisms. Furthermore, exposure of PC-12 cells to bradykinin did not increase intracellular cAMP levels. The combination of bradykinin and PMA treatments produced only partial additivity in tyrosine hydroxylase activity and phosphorylation. No additivity was produced with bradykinin and high K-treatment. Phosphopeptide analysis was performed on tyrosine hydroxylase obtained from PC-12 cells treated with bradykinin. Bradykinin treatment produced a significant incorporation of [32P]-phosphate into two phosphopeptides of tryptically digested tyrosine hydroxylase. One of these peptides corresponds to a peptide obtained by trypsinization of purified tyrosine hydroxylase that is phosphorylated by purified calcium/calmodulin-dependent protein kinase. The other 32P-tyrosine hydroxylase-peptide obtained from PC-12 cells treated with bradykinin corresponds to the phosphorylation site obtained during PMA stimulation of PC-12 cells. These results indicate that bradykinin treatment increases intracellular inositol phosphates, calcium, and possibly diacylglycerol levels in PC-12 cells. These effects could then increase calcium/calmodulin-dependent protein kinase activity and possibly calcium/phospholipid-dependent protein (protein kinase C) activity, resulting in increased phosphorylation and activity of tyrosine hydroxylase.
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PMID:Regulation of tyrosine hydroxylase activity in pheochromocytoma PC-12 cells by bradykinin. 196 17

The purpose of this study was to examine the effects of angiotensin on the enzyme activities and gene expression of two catecholamine synthesizing enzymes, tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT), in bovine adrenal medullary (AM) cells. Short term (15 min) incubation of cultured AM cells with 2 nM [Sar1]angiotensin II (s1-AII) did not increase basal secretion of catecholamines; however, longer incubations (3, 24, or 72 h) produced 4-10-fold increases. To determine whether angiotensin affects synthesis of catecholamines, the activities of TH and PNMT were examined. Incubation with s1-AII (15-30 min) decreased the Km of TH for its biopterine cofactor [6R)-5,6,7,8-tetrahydro-1-biopterin dihydrochloride (BH4] without affecting the Vmax, suggesting activation of TH. After long term incubation (72 h) the Km value was identical to that of control, while increases in the apparent Vmax were observed. PNMT activity was unaffected during a 30-min treatment with s1-AII; however, 2-fold increases occurred after a 48-72-h incubation. s1-AII (24 h) increased the relative abundance of TH and PNMT mRNAs, suggesting that the long term increase in enzyme activities reflected increased expression of TH and PNMT genes. Maximal increases were observed at 2 nM s1-AII and the changes were antagonized by saralasin. Induction of TH mRNA by s1-AII was additive to the effects of veratridine or forskolin indicating that effects of angiotensin were not due to membrane depolarization or increased cyclic AMP levels. Incubation with Ca2+ ionophore A23187 increased TH and PNMT mRNA levels in AM cells raising the possibility that the increase in cellular [Ca2+] could mediate effects of angiotensin. Angiotensin-induced increases in TH and PNMT mRNA were inhibited by nifedipine indicating involvement of voltage-dependent Ca2+ channels. In addition, the increases in TH, but not PNMT mRNA, were antagonized by dantrolene, which inhibits mobilization of Ca2+ from intracellular stores. Calmodulin involvement was suggested by the inhibition of s1-AII induced changes in mRNA with 1 microM calmidazolium.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Short and long term regulation of catecholamine biosynthetic enzymes by angiotensin in cultured adrenal medullary cells. Molecular mechanisms and nature of second messenger systems. 196 64

Rats on calcium-deficient diets developed hypocalcemia, hyperparathyroidism and hypertension and showed an increase in plasma catecholamines. Adrenal gland catecholamines were decreased while tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) were found to be increased, as compared to controls. In contrast, no significant differences were found between controls and parathyroidectomized rats in plasma catecholamines, and catecholamines, TH and DBH of the adrenal gland. These findings seem to indicate that the genesis of hypertension in rats on a low calcium diet is secondary to hyperparathyroidism caused by a low calcium diet. Furthermore, some relation between catecholamines and parathyroid hormone seems to exist in the regulation of blood pressure in rats.
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PMID:Dietary calcium deprivation increased the levels of plasma catecholamines and catecholamine-synthesizing enzymes of adrenal glands in rats. 196 34

The site specificity of tyrosine hydroxylase phosphorylation in intact PC12 cells, labeled with 32Pi, was investigated. Digestion of 32P-tyrosine hydroxylase with trypsin produced five distinct 32P-labeled peptides (termed PC-1 through PC-5). Sequencing of the peptides revealed four acceptor sites: Ser8, Ser19, Ser31, and Ser40. The phosphorylation site in peptides PC-1 (AV-SEQDAK) and PC-2 (RAVSEQDAK) was identified as Ser19. Agents which cause calcium influx increased 32P incorporation into tyrosine hydroxylase at Ser19. PC-3 was identified as QAEAVTSPR, which contains the phosphorylation site Ser31. Nerve growth factor and phorbol dibutyrate increased 32P incorporation into Ser31. PC-4 was identified as the N-terminal amino acid sequence ((M)PTPSAPSPQPK), and the 32P incorporation occurred at Ser8. Of the agents tested, only okadaic acid (a protein phosphatase inhibitor) increased the phosphorylation of Ser8. PC-5 was shown to contain Ser40. Treatment of the PC12 cells with cAMP-acting agents increased 32P incorporation into Ser40. The present results demonstrate that some, but not all, of the phosphorylation sites demonstrated previously in vitro exist in situ. Conversely, the identification of Ser31 establishes a physiological phosphorylation site not previously reported in vitro. These four sites account for most, if not all, of the diversity in tryptic phosphopeptides reported previously for rat tyrosine hydroxylase.
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PMID:Phosphorylation of tyrosine hydroxylase in situ at serine 8, 19, 31, and 40. 197 63

Membrane depolarization has been widely used to elucidate the response of the nervous system to prolonged neuronal activity or stress. We studied the effect of treating PC12 cells with membrane depolarizing stimuli, 50 mM KCl, or 150 microM veratridine, and the subsequent changes in the mRNA levels of the catecholamine biosynthetic enzymes, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH). TH mRNA levels were found to increase 2- to 5-fold after continuous treatment for 1-12 h with 50 mM KCl. Depolarization with 150 microM veratridine had a similar effect on TH mRNA. In contrast, DBH mRNA levels were unchanged by either KCl or veratridine treatment. The role of calcium in the increase of TH mRNA levels elicited by depolarization was examined. The increase in TH mRNA was inhibited by the chelation of calcium with 3 mM EGTA. However, in contrast to their effect on phosphorylation of TH elicited by acute depolarization, the calcium channel blockers, nitrendipine and verapamil, and the calmodulin antagonists, W7 and trifluoperazine, did not prevent the increase in TH mRNA levels subsequent to several hours exposure to depolarizing stimuli. The calcium ionophore, A23187, alone was unable to induce TH mRNA levels. Thus, the increase in TH mRNA elicited by depolarization is mediated differently than the acute phosphorylation of the enzyme.
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PMID:Differential effect of membrane depolarization on levels of tyrosine hydroxylase and dopamine beta-hydroxylase mRNAs in PC12 pheochromocytoma cells. 197 98

In the present study we have investigated whether sauvagine (SVG) and urotensin I (UT), two peptides displaying sequence homology with corticotropin-releasing factor (CRF), could affect synaptosomal tyrosine hydroxylase (TH) activity of mouse striatum in a manner similar to CRF. The enzyme activity was assayed in supernatants obtained following sonication and centrifugation of homogenates preincubated with the peptides. SVG and UT produced a concentration-dependent increase of TH activity with a half-maximal effect obtained at 5 and 10 nM, respectively. SVG and UT were as effective as CRF with maximal stimulations corresponding to 52-58% increase of basal enzyme activity, whereas the rank order of potency was SVG greater than UT = CRF. Kinetic analysis of TH activity versus low concentrations of the pterin co-factor (0.05-0.4 mM) indicated that the stimulations elicited by CRF, SVG and UT were associated with an increase in the Vmax of the enzyme form with high affinity for the co-factor. The CRF receptor antagonist alpha-helical CRF9-41 inhibited the effects of all 3 peptides. Moreover, the combined addition of CRF with either SVG or UT did not produce additive effects on TH activity. The stimulatory effects of CRF, SVG and UT were dependent on the concentration of extracellular free Ca2+, being minimal in a Ca2(+)-free medium and maximal at about 0.5 mM extracellular free Ca2+. These results indicate that SVG and UT can mimic the effect of CRF on synaptosomal TH by acting on a common receptor site associated with a Ca2(+)-dependent mechanism.
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PMID:CRF-like effects of sauvagine and urotensin I on synaptosomal tyrosine hydroxylase activity of mouse striatum. 197 15

These studies were carried out to characterize the activation of rat striatal tyroxine hydroxylase produced by depolarization of the medial forebrain bundle and to evaluate the possible role of cyclic AMP as a mediator of this activation. The enzymatic properties of tyrosine hydroxylase following in vivo depolarization were compared to those produced by treatment of striatal synaptosomes with dibutyryl cyclic AMP (dbcAMP). Similar effects were observed with regard to enzyme distribution, altered sensitivity to dopamine-induced inhibition, and activity as a function of tyrosine concentration. However, differences between the two treatments were also apparent. First, treatment with dbcAMP shifted the pH optimum from 6.2 to 7.0. In contrast, electrical stimulation decreased the rate of decline in activity as the pH was increased above the optimum, but did not shift the pH optimum. Second, plots of tyrosine hydroxylase activity versus cofactor concentration revealed two enzyme forms for both control and electrically stimulated preparations. However, dbcAMP treatment converted the enzyme to a single high affinity form. These results can be explained by one of the following: (1) cyclic AMP is the sole mediator of enzyme activation, but does not produce a maximally activated enzyme following in vivo depolarization, (2) cyclic AMP is only one of several mediators involved or (3) cyclic AMP is not involved in depolarization-induced activation, with activation occurring via the mediation of other intracellular messengers, such as calcium.
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PMID:Activation of striatal tyrosine hydroxylase by in vivo electrical stimulation: comparison with cyclic AMP-mediated activation. 198 54

1. The membrane properties of substantia nigra pars compacta neurones were studied using an in vitro slice preparation of guinea-pig midbrain. 2. Neurones were divided into two classes based on their electrophysiological properties: bursting neurones displayed a burst of several rapidly accommodating action potentials in response to relaxation of hyperpolarizing current injected through the microelectrode, while non-bursting neurones produced regularly spaced action potentials. These neuronal types were found to be electrophysiologically distinct from those recorded in the substantia nigra pars reticulata and the subthalamic nucleus. 3. Non-bursting neurones, which comprised ca 85% of the sampled cells, were characterized by a slow, pacemaker pattern of firing at rest, broad action potentials, a pronounced spike after-hyperpolarization, long membrane time constants, and strong transient outward and time-dependent inward rectification. 4. Bursting neurones, comprising ca 15% of the sample, displayed rapid firing rates at rest, fast action potentials, a shallow spike after-hyperpolarization and briefer membrane time constants. All of these parameters were significantly different from those of the non-bursting type. Bursting neurones lacked transient outward or time-dependent inward rectification. 5. Both types of cells were capable of generating pronounced calcium-dependent, low-threshold spikes in the presence of tetrodotoxin (TTX). However, only the non-bursting type displayed calcium-dependent rhythmic oscillations in membrane potential near resting potential in the presence of TTX. The firing rate, action potential shape and after-hyperpolarization of non-bursting neurones were strongly influenced by calcium-dependent currents. 6. The majority of cells were injected with biocytin, which allowed morphological reconstruction of the neurones and confirmation of their location within the pars compacta. Non-bursting neurones had variable soma shapes and their dendrites were mostly directed in a medio-lateral direction. Many cells extended some of their dendrites into the pars reticulata. Bursting neurones were mainly fusiform in shape with their dendrites oriented in a medio-lateral direction; a few had dendrites extending into the pars reticulata. 7. Thirty-six neurones were also double labelled using a combination of biocytin or Lucifer Yellow injection with tyrosine hydroxylase (TH) immunohistochemistry. Non-bursting neurones all displayed TH immunofluorescence, while none of the bursting neurones were TH positive.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Electrophysiology of dopaminergic and non-dopaminergic neurones of the guinea-pig substantia nigra pars compacta in vitro. 206 49


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