Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The main diarrheic shellfish poisoning (DSP) toxin is okadaic acid (OA). Although OA is a protein phosphatase 1 and 2A inhibitor less is known about the involvement of the toxin in diarrhea. The initial statement was that OA, by altering the phosphorylation state of proteins, might modify glucose uptake and consequently ionic and water reabsorption across the small intestine. This report presents studies of glucose transport in isolated rabbit enterocytes by using a fluorescent derivative of D-glucose. The dye allowed examining the relation between the toxic effect of OA and cellular mechanisms involved in glucose transport. The central findings are: (i) OA potentiates decrease on glucose uptake due to protein kinase A (PKA) inhibitors such as H89; and (ii) the increase of sugar uptake induced by the protein kinase C (PKC) inhibitor chelerythrine is enhanced by OA. Importance of this work is justified by the need to determine molecular targets of diarrheic toxins in intestinal cells.
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PMID:Glucose uptake in enterocytes: a test for molecular targets of okadaic acid. 1462 48

To examine the changes in heat shock proteins (HSPs) and calcineurin (CaN), a calcium/calmodulin regulated protein phosphatase, in hypertrophied rat skeletal muscles, adult male Wistar rats were administered clenbuterol (CLB, 30 mg l(-1) in drinking water), a beta 2-agonist, for 4 weeks. Compared to controls, CLB-treated rats had significantly larger body (10%) and relative (to body weight) soleus (Sol, 16%), plantaris (Plt, 32%) and gastrocnemius (Gast, 27%) weights. Immunohistochemically classified fast fibers were hypertrophied in the Sol (64%), Plt (62%), and deep (d, 70%) and superficial (s, 44%) regions of the Gast, whereas slow fibers were hypertrophied only in the Plt (47%). The percentage of fast fibers in the Sol increased from 10% to 21%. The myosin heavy chain (MHC) isoform composition shifted from slow to fast in the Sol (increase in the percentage of type IIa MHC and de novo synthesis of type IIx MHC) and Gast-d (de novo synthesis of type IIb MHC) and to the faster isoforms in the Plt (increase in the percentage of type IIb MHC). Hsp72 and Hsp90 levels in CLB-treated rats were 52% and 50% lower in the Sol and 44 and 41% lower in the Gast-d, respectively, than in control rats. In control rats, the relative content of CaN was: Sol>Gast-d>Plt>Gast-s, and CLB treatment enhanced the CaN content by 1.4-, 1.2-, 5.0-, and 3.3-fold, respectively. These results indicate that the down-regulation of HSPs in the Sol and Gast-d was closely related to a decrease in the slow phenotype, and that the relative up-regulation of CaN among the muscles/regions was closely related to the selective hypertrophy of fast fibers in the CLB-treated rats.
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PMID:Calcineurin and heat-shock proteins modulation in clenbuterol-induced hypertrophied rat skeletal muscles. 1475 79

Microcystins, toxic cyclic heptapeptides and nodularin-R, a toxic cyclic pentapeptide, were determined using liquid chromatography (LC) with detection using photo-diode array ultra-violet (PDA-UV) and protein phosphatase (PP) assay. Positive fractions were analysed for toxins using collision-induced dissociation (CID) and tandem MS/MS experiments which were carried out simultaneously using electrospray ion-trap instrumentation. Reversed-phase liquid chromatography (LC) using an acetonitrile/water gradient was used for the LC-MS(2) determination of six microcystins standards and nodularin. The molecular related ion species, [M+H](+)([M+2H](2+) in the case of MC-RR), were used as the precursor ions for MS(2) experiments. Optimum calibration and reproducibility data were obtained for MC-LR using LC-MS(2); 0.1-5.0 microg/ml, r2 = 0.992 (n = 3); % RSD < or =7.3 at 0.25 microg MC-LR/ml (n = 3). The detection limit (S/N = 3) was better than 0.1 ng. Water samples for microcystin analysis were first screened using protein phosphatase (PP) assays and positives were concentrated using C-18 solid-phase extraction. The developed method was applied to examine a lake in Ireland contaminated by Microcystis sp. and MC-LR and MC-LA were identified.
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PMID:Determination of toxic cyclic heptapeptides by liquid chromatography with detection using ultra-violet, protein phosphatase assay and tandem mass spectrometry. 1508 82

Lake Oubeira has been used as the main source of drinking water for many communities in the East of Algeria. In this lake, nutrient loading coupled with year-round warm weather favors the growth of cyanobacteria, several of which can produce cyanotoxins, especially the potent liver toxins called microcystins (MCYSTs). The present study evaluated microcystin levels and characterized the different microcystin variants present in the raw water during a 17-month period (April 2000-September 2001), as measured by protein phosphatase inhibition assays and by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry, respectively. The results showed that microcystin concentrations in the lake water varied between 3 and 29,163 microg microcystin-LR equivalent per liter. The microscopic examination of the phytoplankton samples showed the dominance of the Microcystis genus in the cyanobacterial bloom. The highest MCYST concentration was observed in August 2001, at 29,163 microg/l. Therefore, the highest total MCYST content per phytoplankton biomass was found in August 2001, with 4,590 microg MCYST-LR equivalents/g dried bloom material. Analysis of the field bloom extract by MALDI-TOF mass spectrometry demonstrated the presence of four variants of microcystins: microcystin-LR (MCYST-LR), microcystin-YR (MCYST-YR), microcystin-RR (MCYST-RR), and a demethylated variant of MCYST-LR (D-MCYST-LR).
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PMID:First report of a microcystin-containing bloom of the cyanobacteria Microcystis spp. in Lake Oubeira, eastern Algeria. 1510 70

Adenylyl cyclase (AC) subtypes have been implicated in memory processes and synaptic plasticity. In the present study, the effects of aging and learning on Ca2+/calmodulin-stimulable AC1, Ca2+-insensitive AC2 and Ca2+/calcineurin-inhibited AC9 mRNA level were compared in the dorsal hippocampus of young-adult and aged C57BL/6 mice using in situ hybridization. Both AC1 and AC9 mRNA expression were downregulated in aged hippocampus, whereas AC2 mRNA remained unchanged, suggesting differential sensitivities to the aging process. We next examined AC mRNA expression in the hippocampus after spatial learning in the Morris water maze. Acquisition of the spatial task was associated with an increase of AC1 and AC9 mRNA levels in both young-adult and aged groups, suggesting that Ca2+-sensitive ACs are oppositely regulated by aging and learning. However, aged-trained mice had reduced AC1 and AC9, but greater AC2, mRNA levels relative to young-trained mice and age-related learning impairments were correlated with reduced AC1 expression in area CA1. We suggest that reduced levels of hippocampal AC1 mRNA may greatly contribute to age-related defects in spatial memory.
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PMID:Effects of age and spatial learning on adenylyl cyclase mRNA expression in the mouse hippocampus. 1521 34

The pH dependent activation of calcineurin by exogenous metal ion was studied over the pH range from 6.5 to 9.0 in increments of 0.5 pH units. Calcineurin activated by Co2+, Ni2+, or Mg2+ was characterized and compared to the pH dependency of the Mn(2+)-activated enzyme (Martin, B.L., and Graves, D.J. (1986) J. Biol. Chem. 261, 14545-14550). The pH dependency of the kinetic parameters varied with metal ion and subsequent analysis yielded estimates for the pKa values for the enzyme-metal ion and the enzyme-metal ion-substrate complexes with each of the exogenous metal ions characterized. The evaluated pK(a)s for enzyme-metal ion (EM) complexes showed an inverse relationship with the pK(a)s of the M(2+)-H2O complex. In contrast, variation of the pK(a)s for the enzyme-metal ion-substrate (EMS) complexes showed no trend. These data support the hypothesis that exogenous metal ion functions to facilitate a proton transfer before the turnover of substrate with the acidity of the exogenous metal ion as a primary determinant of its participation.
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PMID:Acidity of exogenous metal ion in the activation of calcineurin. 1525 60

We showed previously that exposure to microcystin-LR causes renal toxic effects in isolated perfused rat kidney, and that inflammatory mediators from supernatants of macrophages stimulated by microcystin-LR are involved in this process. The aim of this research was to examine water and electrolytes secretion in vivo, induced by microcystin-LR and supernatant of macrophages stimulated for this toxin (SUP.MphiS + MCLR), using perfused rat ileal segment and ligated intestinal loop models. We found microcystin-LR at 1 microg/ml (0.09 +/- 0.003* vs. control 0.07 +/- 0.001 g of secretion/2 cm of loop; P < 0.05*) and the SUP.MphiS + MCLR after 18 h postinoculation (0.10 +/- 0.003 vs. control 0.03 +/- 0.002 g/cm) caused intestinal secretion. In addition, microcystin-LR caused significant sodium secretion (-2.18 +/- 0.72* vs. control 2.18 +/- 0.50 microEq g(-1) min(-1)), potassium (-0.26 +/- 0.04* vs. control 0.32 +/- 0.03 microEq g(-1) min(-1)), chloride (MCLR = -3.29 +/- 1.93* vs. control 0.88 +/- 1.25 microEq g(-1) min(-1)) and water (-0.012 +/- 0.004* vs. control 0.002 +/- 0.002 ml g(-1) min(-1)). We also demonstrated SUP.MphiS + MCLR to induce intestinal secretion of electrolytes (sodium, potassium, chloride) and water. These findings suggested that microcystin-LR and lamina propria macrophages-derived mediators are able to induce intestinal secretion in vivo, probably via inhibition of protein phosphatase.
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PMID:Microcystin-LR promote intestinal secretion of water and electrolytes in rats. 1545 Sep 31

Surface-enhanced laser desorption ionization mass spectrometry (SELDI-TOFMS) was used to develop a new and useful method for determination and identification of the cyanobacterial (blue-green algae) toxins: microcystin and nodularin. The technique, combining chromatography and MS, enables microcystin/nodularin capture, purification, analysis, and processing from complex biological mixtures directly onto a hydrophobic chip. Factors affecting ion intensities, including matrix concentration and laser intensity, were investigated to optimize sensitivity of the method. Microcystins and nodularin were analyzed for femtomolar sensitivity (about 2.5 pg microcystin-LR in 2 microl water). Samples of blood sera and liver tissue were spiked with microcystin-LR and analyzed. The detection limit was 1 ng in 2 microl blood sera solution. Reactions of microcystins by compounds containing mercaptan groups, such as dithiothreitol, aminoethanethiol and protein phosphatase 1, were examined on the chip by mass spectrometry. Formation of the microcystin-dithiothreitol conjugate was used to confirm the target compounds. The MS/MS data obtained showed the presence of the microcystin conjugate. The reaction position of the toxin with target compound was confirmed by a series of MS/MS fragment ions. The protein profile of microcystins reacting with protein phosphatase 1 was also obtained from the SELDI-TOF mass spectra.
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PMID:Detection and analysis of the cyanobacterial peptide hepatotoxins microcystin and nodularin using SELDI-TOF mass spectrometry. 1545 Sep 32

The cyclic peptide toxins microcystins and nodularins are the most common and abundant cyanotoxins present in diverse water systems. They have been the cause of human and animal health hazards and even death. Development of suitable chemoprotectants against microcystin is essential considering the human health importance. In the present study, three agents cyclosporin-A (10mg/kg), rifampin (25mg/kg) and silymarin (400mg/kg) pre-treatment gave 100% protection against lethal dose of microcystin-LR (100 microg/kg). Various biochemical parameters were evaluated to study the recovery profile of protected animals at 1, 3, 7 and 14 days post-toxin treatment. There was significant depletion of hepatic glutathione in protected animals compared to control group till 7 days post-treatment but normalised by 14 days. Similarly enhanced hepatic lipid peroxidation, inhibition of protein phosphatase activity was observed till 3-7 days post-treatment in protected animals. Elevated levels of enzymes alanine amino transferase, lactate dehydrogenase and sorbitol dehydrogenase were observed in serum at 1 day post-treatment. All the biochemical variables reached control levels by 14 day post-treatment. Immunoblotting analyses of liver homogenates showed microcystin-protein phosphatase adduct in liver samples of toxin treated as well as antidote-protected animals. The adduct could be seen even after 14 days post-toxin treatment. The study shows that though cyclosporin-A, rifampin and silymarin could offer 100% protection against microcystin-LR induced lethality many of the toxic manifestations are persistent and could not be reversed till 7 days.
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PMID:Protective efficacy and the recovery profile of certain chemoprotectants against lethal poisoning by microcystin-LR in mice. 1550 Aug 48

Cyanobacteria are known producers of cytotoxins, hepatotoxins, and neurotoxins. The main toxins are microcystins, cyclic heptapeptide hepatotoxins, produced by strains of several cyanobacterial genera frequently found in eutrophied freshwaters. Due to the acute and chronic toxicity of microcystins, successful removal of these toxins in drinking water treatment processes is of increasing concern. In the present work the kinetics of microcystin-LR (MC-LR) oxidation by chlorine dioxide (ClO2) was studied with UV-spectrometry and high performance liquid chromatography (HPLC). Characterization of reaction products was performed with mass spectrometric (MS) analysis, while the toxicity of reaction products was tested with a protein phosphatase inhibition assay (PPIA). The main reaction products formed, dihydroxy isomers of MC-LR as identified by MS, were nontoxic according to the PPIA. The overall rate constant k for the reaction between MC-LR and ClO2 at 293 K and pH 5.65 was modest, k = 1.24 M(-1) s(-1), suggesting that ClO2 is not a suitable oxidant for the degradation of microcystins in drinking water treatment processes.
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PMID:Oxidation of the cyanobacterial hepatotoxin microcystin-LR by chlorine dioxide: reaction kinetics, characterization, and toxicity of reaction products. 1557 2


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