Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incidence of amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) among the Chamorros in Guam is remarkably high. The patients with ALS have clinical and pathological characteristics similar to those in other parts of the world. The PDC patients display parkinsonism and progressive dementia and show a characteristic neuronal loss in certain parts of the central nervous system such as the hippocampus and substantia nigra. The Guamanian patients with ALS and PDC commonly have widespread Alzheimer's neurofibrillary changes, but without the associated senile plaques. We have applied immunohistochemical procedures to examine the expression of marker substances in Guamanian ALS and PDC. The markers studied include tau protein, ubiquitin, beta proteins, synaptophysin, calcineurin, Met-enkephalin, substance P and tyrosine hydroxylase. The results were compared with the findings in patients with Alzheimer's disease, Parkinson's disease, sporadic ALS and familial ALS.
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PMID:Amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam: immunohistochemical studies. 158 17

Tyrosine hydroxylase, which catalyzes the initial step in catecholamine biosynthesis, is phosphorylated at serines 8, 19, 31, and 40 in intact pheochromocytoma (PC12) cells (Haycock, J.W. (1990) J. Biol. Chem. 265, 11682-11691). After 32Pi labeling of rat corpus striata in vivo or rat corpus striatal synaptosomes, 32P incorporation into tyrosine hydroxylase occurred predominantly at serines 19, 31, and 40. Electrical stimulation (30 Hz, 20 min) of the medial forebrain bundle (containing the afferent dopaminergic fibers) increased 32P incorporation into each of the three sites. Brief depolarization of the synaptosomes with elevated [K+]o (20-60 mM, 5-30 s) or veratridine (50 microM, 2 min) produced a selective increase in 32P incorporation into Ser19. Phorbol 12,13-dibutyrate (1 microM, 5 min) increased 32P incorporation into Ser31, and cAMP-acting agents such as forskolin (10 microM, 5 min) increased 32P incorporation into Ser40. In contrast, 32P incorporation into Ser8, which was usually detectable but very low, was not regulated either in vivo or in situ by any of the activators of signal transduction pathways. In synaptosomes, the only treatment found to increase Ser8 phosphorylation was okadaic acid (a protein phosphatase inhibitor), which increased 32P incorporation into all four phosphorylation sites. Thus, three different signal transduction systems appear to mediate the physiological regulation of tyrosine hydroxylase phosphorylation at three different sites.
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PMID:Tyrosine hydroxylase in rat brain dopaminergic nerve terminals. Multiple-site phosphorylation in vivo and in synaptosomes. 167 15

This study examined tyrosine hydroxylase (TH) activity in the stalk-median eminence (SME) and TH messenger RNA (mRNA) signal levels in the arcuate nuclei of the hypothalamus during early, middle, and late pregnancy and related these to circulating levels of ovarian steroids. In addition, this study evaluated the intracellular mechanism(s) which contributes to the semicircadian rhythm in tuberoinfundibular dopaminergic neuronal activity during early pregnancy. The catalytic activity of TH in the SME was determined from the in vitro rate of 3,4,dihydroxyphenylalanine accumulation after inhibiting DOPA decarboxylase with brocresine. TH mRNA signal levels were evaluated by in situ hybridization. TH mRNA signal levels in the arcuate nuclei were 30% lower at 1000 h on day 20 of pregnancy as compared to days 7 and 11, whereas TH activity in the SME at 1000 h was not significantly different on days 7, 11, 16, and 20. Serum PRL levels were low (3-6 ng/ml) and unchanged at 1000 h on days 7, 11, 16, and 20. Circulating progesterone levels increased from 111 to 191 ng/ml on days 7 and 16, respectively, and then declined to 69 ng/ml by day 20. Serum estradiol levels increased from 38 to 106 pg/ml on day 7 and 16, respectively, and then remained elevated on day 20. Thus, the reduction in TH mRNA signal levels during late pregnancy is temporally related to the increased estradiol/progesterone ratio. Elevated serum PRL levels at 0330 h and 1800 h on day 7 were characteristic of the nocturnal and diurnal PRL surges of early pregnancy. Circulating PRL levels were low during the intersurge times (2330 and 1000 h) on day 7 and at all times examined on day 11. TH activity in the SME on day 7 was lower during the PRL surges as compared to the intersurge times, whereas TH activity on day 11 was similar at all times and comparable to the intersurge levels of early pregnancy. Okadaic acid, a protein phosphatase inhibitor, reversed the reduction in TH activity during the nocturnal and diurnal PRL surges, but did not significantly alter TH activity during the intersurge period on day 7. TH mRNA signal levels in the arcuate nuclei were similar throughout day 7. These data indicate that protein dephosphorylation, but not changes in the TH gene expression, may contribute to the semicircadian rhythm in TH activity during early pregnancy.
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PMID:Mechanisms of tyrosine hydroxylase regulation during pregnancy: evidence for protein dephosphorylation during the prolactin surges. 168 38

This article focuses on the role of protein phosphorylation, especially that mediated by protein kinase C (PKC), in neurotransmitter release. In the first part of the article, the evidence linking PKC activation to neurotransmitter release is evaluated. Neurotransmitter release can be elicited in at least two manners that may involve distinct mechanisms: Evoked release is stimulated by calcium influx following chemical or electrical depolarization, whereas enhanced release is stimulated by direct application of phorbol ester or fatty acid activators of PKC. A markedly distinct sensitivity of the two pathways to PKC inhibitors or to PKC downregulation suggests that only enhanced release is directly PKC-mediated. In the second part of the article, a framework is provided for understanding the complex and apparently contrasting effects of PKC inhibitors. A model is proposed whereby the site of interaction of a PKC inhibitor with the enzyme dictates the apparent potency of the inhibitor, since the multiple activators also interact with these distinct sites on the enzyme. Appropriate PKC inhibitors can now be selected on the basis of both the PKC activator used and the site of inhibitor interaction with PKC. In the third part of the article, the known nerve terminal substrates of PKC are examined. Only four have been identified, tyrosine hydroxylase, MARCKS, B-50, and dephosphin, and the latter two may be associated with neurotransmitter release. Phosphorylation of the first three of these proteins by PKC accompanies release. B-50 may be associated with evoked release since antibodies delivered into permeabilized synaptosomes block evoked, but not enhanced release. Dephosphin and its PKC phosphorylation may also be associated with evoked release, but in a unique manner. Dephosphin is a phosphoprotein concentrated in nerve terminals, which, upon stimulation of release, is rapidly dephosphorylated by a calcium-stimulated phosphatase (possibly calcineurin [CN]). Upon termination of the rise in intracellular calcium, dephosphin is phosphorylated by PKC. A priming model of neurotransmitter release is proposed where PKC-mediated phosphorylation of such a protein is an obligatory step that primes the release apparatus, in preparation for a calcium influx signal. Protein dephosphorylation may therefore be as important as protein phosphorylation in neurotransmitter release.
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PMID:The role of protein kinase C and its neuronal substrates dephosphin, B-50, and MARCKS in neurotransmitter release. 168 57

A comparative topographical immunohistochemical analysis was performed on the basal ganglia (including the substantia nigra) in Guamanian parkinsonism-dementia complex, idiopathic Parkinson's disease (PD), and Alzheimer's disease (AD). The striatal projection neurons and their efferent fibers were examined by using antibodies to calcineurin, methionine-enkephalin, and substance P. Tyrosine hydroxylase served as a marker for nigrostriatal dopaminergic neurons. The basal ganglia of patients with parkinsonism-dementia complex reacted strongly with all of the antibodies and the reaction products exhibited a normal distribution pattern. These findings suggest that the striatal output system is well preserved in patients with this disease. Similar results were obtained in patients with AD or PD. However, as compared to the patients with AD or PD, patients with parkinsonism-dementia complex showed severe reduction (greater than 90%) in the number of dopaminergic neurons in both the lateral and the medial portions of the substantia nigra. In view of the functional cortico-subcortical loops, these findings could explain the parkinsonian features and in part the cognitive impairment that occur in parkinsonism-dementia complex on Guam.
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PMID:Immunohistochemical study of the striatal efferents and nigral dopaminergic neurons in parkinsonism-dementia complex on Guam in comparison with those in Parkinson's and Alzheimer's diseases. 169 18

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

An immunohistochemical topographic study was carried out in the putamen from three patients with striatonigral degeneration (SND) using antibody to calcineurin (CaN), a neurochemical marker for the striatal medium-size spinous neurons. In patients with SND, there was significant depletion of CaN immunoreactivity in the putamen with the caudal and lateral portion of the putamen being consistently and severely affected. In addition, the SND patients showed an inhomogeneous distribution pattern of residual CaN staining in the putamen, where remaining CaN immunoreactivity appeared as a characteristic patchwork of "islands" resembling the "striosomes" observed by the tyrosine hydroxylase or Met-enkephalin immunostaining in the putamen from normal individuals. This finding may account for the fact that there are subregional and compartmental differences in susceptibility of the medium-sized spinous neurons in the putamen with SND.
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PMID:Inhomogeneity of the putaminal lesion in striatonigral degeneration. 197 51

A topographical immunocytochemical analysis was performed on the substantia nigra from patients with idiopathic Parkinson's disease and striatonigral degeneration. Antibodies to tyrosine hydroxylase, a marker for nigrostriatal dopaminergic neurons, and to calcineurin, a marker for striatonigral projection fibers, were used in this study. There was a marked depletion of dopaminergic neurons in the substantia nigra of parkinsonian patients compared with control subjects, the reduction being greater in the lateral portion than in the medial portion (p less than 0.001). Calcineurin immunoreactivity was densely distributed throughout the substantia nigra of patients with Parkinson's disease and control subjects. The numbers of dopaminergic neurons and of calcineurin-immunoreactive fibers were markedly reduced in the lateral portion of the substantia nigra in all patients with striatonigral degeneration. Our results suggest that many symptoms of these two diseases may be due to disruption of the functions of the putamen and the lateral portion of the substantia nigra, which have dense reciprocal connections as part of the dopamine-related nigrostriatal loop.
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PMID:Subdivisional involvement of nigrostriatal loop in idiopathic Parkinson's disease and striatonigral degeneration. 255 95

We have developed a cell-free assay to detect and characterize nerve growth factor (NGF)-activated protein kinase activity. Cultured PC12 cells were briefly exposed to NGF, and extracts of these were assayed for phosphorylating activity using exogenously added tyrosine hydroxylase as substrate. Tyrosine hydroxylase was employed since it is an endogenous substrate of NGF-regulated kinase activity and is activated by phosphorylation. In the cell-free assay, extracts prepared from NGF-treated cells yielded a 2-3-fold greater incorporation of phosphate into tyrosine hydroxylase as compared with extracts of control, NGF-untreated cells. Activation did not occur, however, if NGF was added directly to cell extracts. The NGF-stimulated phosphorylating activity appeared to be due to regulation of a protein kinase rather than of a phosphoprotein phosphatase. Characterization of the kinase (designated as kinase N) showed that it is soluble, is detectably activated within 1-3 min after cells are exposed to NGF and maximally activated by 10 min, is half-maximally activated with 0.5 nM NGF and maximally activated with 1 nM NGF, is detectable in the presence of either Mg2+ or Mn2+ but does not require Ca2+, does not require nonmacromolecular cofactors, can use histone H1 as a substrate, and exhibits a 2-fold increase in apparent Vmax in response to NGF but does not undergo a significant change in apparent Km for either ATP or GTP. A number of characteristics of kinase N were assessed including susceptibility to inhibitors, substrate specificity, cofactor requirements, ATP dependence, and lack of down-regulation by prolonged expose to a phorbol ester. These studies indicated that it lacks tyrosine kinase activity and is distinct from a variety of well-characterized protein kinases including cAMP-dependent protein kinase, protein kinase C (Ca2+/phospholipid-dependent enzyme), Ca2+/calmodulin-dependent kinase, and casein kinase II. Preliminary purification data show that the kinase has a basic pI and that it has an apparent Mr of 22,000-25,000. The only amino acid in tyrosine hydroxylase found to be phosphorylated by the semipurified kinase is serine.
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PMID:Cell-free detection and characterization of a novel nerve growth factor-activated protein kinase in PC12 cells. 358 24

Stimulation of bovine chromaffin cell in culture changed (increased or decreased) the phosphorylation state of several proteins as examined by 32P incorporation. Enhanced phosphorylation of 22 protein bands as well as increased dephosphorylation of a 20.4 kilodaltons protein band was observed when extracts of cultured chromaffin cells stimulated by either acetylcholine or high K+ were subjected to mono-dimensional gel electrophoresis. For several protein bands, the degree of phosphorylation was larger in cells stimulated by acetylcholine than in those challenged by a depolarizing concentration of K+. The most affected phosphoproteins have apparent molecular weights of 14,800, 29,000, 33,000, 57,000 (tubulin subunit), 63,000 (tyrosine hydroxylase subunit) and 94,000. The presence of a low extracellular calcium concentration (0.5 mM Ca2+ plus 15 mM Mg2+) in the incubation medium inhibited (38-100%) the acetylcholine-evoked increases in protein phosphorylation observed previously for 18 protein bands. Trifluoperazine at the concentration required for 50% inhibition of acetylcholine-induced catecholamine release decreases (33-100%) the stimulation-induced phosphorylation in all polypeptides, with the exception of the 14.8 kilodaltons and the dephosphorylated 20.4 kilodaltons components which were not affected. Two-dimensional gel electrophoresis analysis revealed that exposure of chromaffin cells to acetylcholine produced two types of effect on protein phosphorylation: activation of protein kinase activities affecting about 30 polypeptides; activation of protein phosphatase activities resulting in the dephosphorylation of about 40 polypeptides, most of them appearing as minor phosphoproteins, with the exception of the alpha-subunit of pyruvate dehydrogenase and the 20.4 kilodaltons polypeptide. On the basis of their molecular properties (molecular weight and pI) and their abundance in chromaffin cells, the 80 kilodaltons phosphoprotein which focused at pI 4.8 and the 117.5 kilodaltons phosphoprotein which focused at pI 5.0 were identified as chromogranins A and B, respectively. The relationship between acetylcholine-induced protein phosphorylation (or dephosphorylation) and catecholamine secretion was also investigated. The time course of protein phosphorylation (or dephosphorylation) paralleled or preceded [3H]noradrenaline release for 16 phosphoproteins.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Phosphorylation and dephosphorylation of chromaffin cell proteins in response to stimulation. 377 57


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