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)

Preincubation of sarcoplasmic reticulum (SR) membranes with a combination of ATP and NaF resulted in inhibition of Ca2+ accumulation and stimulation of Ca(2+)-ATPase and Ca2+ efflux. Under the same conditions, the activity of the SR phosphoprotein phosphatase was inhibited and the phosphorylation of two polypeptides with apparent molecular masses of 160 and 150 kDa was obtained. The effect of ATP is specific, since the ATP analogue adenosine 5'-[beta gamma-imido]triphosphate did not replace for ATP. In the absence of NaF, ATP was ineffective. The phosphorylation of the 160 kDa and/or 150 kDa proteins and the stimulation of Ca2+ efflux are clearly related. The phosphorylation of both proteins and the increase in Ca2+ efflux show a similar dependence on the concentration of ATP. The level of protein phosphorylation and the stimulation of Ca2+ efflux were also controlled by the NaF concentration which inhibits the phosphatase and of net Ca2+ accumulation, as well as for the stimulation of phosphorylation of both polypeptides. Quantitative analysis revealed a linear correlation between these three activities. Dicyclohexylcarbodi-imide, which inhibited Ca2+ efflux, also inhibited the phosphorylation of the two polypeptides. These results suggest the involvement of the phosphorylation/dephosphorylation of 160 kDa and/or 150 kDa polypeptides in the activation of Ca2+ release from SR membranes.
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PMID:Involvement of protein phosphorylation in activation of Ca2+ efflux from sarcoplasmic reticulum. 203 85

During ATP hydrolysis the K+-translocating Kdp-ATPase from Escherichia coli forms a phosphorylated intermediate as part of the catalytic cycle. The influence of effectors (K+, Na+, Mg2+, ATP, ADP) and inhibitors (vanadate, N-ethylmaleimide, bafilomycin A1) on the phosphointermediate level and on the ATPase activity was analyzed in purified wild-type enzyme (apparent Km = 10 microM) and a KdpA mutant ATPase exhibiting a lower affinity for K+ (Km = 6 mM). Based on these data we propose a minimum reaction scheme consisting of (i) a Mg2+-dependent protein kinase, (ii) a Mg2+-dependent and K+-stimulated phosphoprotein phosphatase, and (iii) a K+-independent basal phosphoprotein phosphatase. The findings of a K+-uncoupled basal activity, inhibition by high K+ concentrations, lower ATP saturation values for the phosphorylation than for the overall ATPase reaction, and presumed reversibility of the phosphoprotein formation by excess ADP indicated similarities in fundamental principles of the reaction cycle between the Kdp-ATPase and eukaryotic E1E2-ATPases. The phosphoprotein was tentatively characterized as an acylphosphate on the basis of its alkali-lability and its sensitivity to hydroxylamine. The KdpB polypeptide was identified as the phosphorylated subunit after electrophoretic separation at pH 2.4, 4 degrees C of cytoplasmic membranes or of purified ATPase labeled with [gamma-32P]ATP.
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PMID:Characterization of the phosphorylated intermediate of the K+-translocating Kdp-ATPase from Escherichia coli. 252 40

The cellular localization of DARPP-32, a dopamine- and cAMP-regulated phosphoprotein of Mr 32,000 that appears to mediate certain actions of dopamine in the mammalian brain by acting as an inhibitor of protein phosphatase 1, was studied in the kidney of several species. DARPP-32 mRNA and DARPP-32-like immunoreactivity were found in the cytoplasm of cells in the thick ascending limb of the loop of Henle. The specific dopamine DA1 agonist SKF 82526 caused a dose-dependent inhibition of Na+,K+-ATPase activity, which could be blocked by SCH 23390, a specific DA1 antagonist, and by PKI-(5-24) amide, a specific inhibitor of cAMP-dependent protein kinase. The results indicate that DA1 dopamine receptors and DARPP-32, an intracellular third messenger for dopamine, are part of the signal-transduction process for dopamine acting on renal tubule cells.
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PMID:Dopamine- and cAMP-regulated phosphoprotein (DARPP-32) and dopamine DA1 agonist-sensitive Na+,K+-ATPase in renal tubule cells. 257 60

Caldesmon is a major calmodulin- and actin-binding protein of smooth muscle which interacts with calmodulin in a Ca2+-dependent manner or with actin in a Ca2+-independent manner. Isolated caldesmon is capable of inhibiting the actin-activated Mg2+-ATPase of smooth-muscle myosin, suggesting a possible physiological role for caldesmon in regulating the contractile state of smooth-muscle. Caldesmon can be phosphorylated in vitro by a co-purifying Ca2+/calmodulin-dependent protein kinase and dephosphorylated by a protein phosphatase, both of which are present in smooth muscle. We investigated further the phosphorylation of caldesmon and the effects which phosphorylation has on the functional properties of the protein. The kinetics of caldesmon phosphorylation were similar whether the caldesmon substrate was free or bound to actin, actin/tropomyosin or thin filaments. Caldesmon containing endogenous kinase activity was rapidly phosphorylated (to approx. 1 mol of Pi/mol of caldesmon in 5 min) when reconstituted with actin, myosin, tropomyosin, calmodulin and myosin light-chain kinase in the presence of Ca2+ and MgATP2-. Under conditions in which unphosphorylated caldesmon showed substantial inhibition of the actin-activated myosin Mg2+-ATPase, no inhibition was observed with phosphorylated caldesmon. This was the case whether caldesmon was phosphorylated before addition to the actomyosin Mg2+-ATPase system, or phosphorylation was allowed to take place during the ATPase reaction. Binding studies revealed maximal binding of 1 mol of unphosphorylated caldesmon/9.5 mol of actin and 1 mol of phosphorylated caldesmon/11.7 mol of actin. All the bound phosphorylated caldesmon could be released by Ca2+/calmodulin, with half-maximal release at 0.11 microM-Ca2+, whereas only 62% of the bound unphosphorylated caldesmon could be removed, with half-maximal release at 0.16 microM-Ca2+. However, under conditions in which inhibition of actomyosin Mg2+-ATPase activity by non-phosphorylated but not by phosphorylated caldesmon was observed, both forms of caldesmon would remain bound to the thin filament. These observations suggest a possible mechanism whereby caldesmon phosphorylation may prevent its inhibitory action on the actomyosin Mg2+-ATPase.
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PMID:The effects of phosphorylation of smooth-muscle caldesmon. 282 3

Concurrent exposures to organophosphorus insecticide leptophos and the industrial solvents n-hexane and toluene were implicated in causing an outbreak of neuropathy in workers. Although both leptophos and n-hexane produce central-peripheral distal axonopathy, the morphology and distribution of neuropathic lesions are distinct, reflecting different modes of action. The molecular mechanisms of organophosphorus compound-induced delayed neurotoxicity (OPIDN) and aliphatic hexacarbon-induced neurotoxicity have been investigated utilizing various biochemical techniques, (i.e. one- and two-dimensional gel electrophoresis, immunoblotting, peptide mapping). Oral administration of tri-o-cresyl phosphate (TOCP) produced delayed neurotoxicity and increased in vitro Ca2+ and calmodulin-dependent kinase protein phosphorylation of cytoskeletal proteins in brain, spinal cord, and sciatic nerve of chickens. This enhanced protein phosphorylation correlated well with the following characteristics of OPIDN: test chemical, whether an OPIDN-producing or not; dose-dependence and time course of the effect; and the animal sex sensitivity, age selectivity, and species susceptibility. The proteins that showed an increased phosphorylation were identified to be; alpha- and beta-tubulin, microtubule-associated protein-2 (MAP-2), and the 3 neurofilament proteins 70 kDa, 160 kDa, and 210 kDa. Further studies suggested that the increased protein phosphorylation is not related to an effect on protein phosphatase or ATPase activity, but rather to altered Ca2+-calmodulin kinase II activity. Aliphatic hexacarbon-induced neurotoxicity is characterized by an accumulation of 10 nm neurofilaments above the nodes of Ranvier in the spinal cord and peripheral nerve. Treatment of rats with 2,5-hexanedione, the active neurotoxic metabolite of n-hexane, produced protein crosslinking in a dose-dependent manner. This treatment also decreased protein phosphorylation of neurofilament proteins as well as MAP-2. These studies demonstrate the involvement of cytoskeletal proteins in the molecular pathogenesis of chemical-induced neurotoxicity.
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PMID:Cytoskeletal proteins as targets for organophosphorus compound and aliphatic hexacarbon-induced neurotoxicity. 283 76

Nanomolar concentrations of synthetic peptides corresponding to the calmodulin-binding domain of skeletal muscle myosin light chain kinase were found to inhibit calmodulin activation of seven well-characterized calmodulin-dependent enzymes: brain 61 kDa cyclic nucleotide phosphodiesterase, brain adenylate cyclase, Bordetella pertussis adenylate cyclase, red blood cell membrane Ca++-pump ATPase, brain calmodulin-dependent protein phosphatase (calcineurin), skeletal muscle phosphorylase b kinase, and brain multifunctional Ca++ (calmodulin)-dependent protein kinase. Inhibition could be entirely overcome by the addition of excess calmodulin. Thus, the myosin light chain kinase peptides used in this study may be useful antagonists for studying calmodulin-dependent enzymes and processes.
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PMID:Synthetic peptides based on the calmodulin-binding domain of myosin light chain kinase inhibit activation of other calmodulin-dependent enzymes. 290 35

A protein kinase inhibitor was found in rat liver cells as a component of HMG proteins. It is located in cytosol as well as in nuclei. It inhibits all tested cAMP independent protein kinases and has no effect on cAMP dependent protein kinases. This inhibitor is a 25 000 Da protein. It has no ATPase, phosphoprotein phosphatase or proteinase activity and is heat unstable.
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PMID:A 25 000 dalton inhibitor of cAMP independent protein kinases present in rat liver HMG protein preparations. 299 59

The Rous sarcoma virus (RSV)-transforming protein, pp60src, is a plasma membrane-associated tyrosine-specific protein kinase. A 36,000-Da cellular polypeptide (p36) which is phosphorylated at tyrosine in RSV-transformed chicken embryo fibroblasts (RSV-CEF) is also plasma membrane associated. To determine if p36 is directly phosphorylation and kinase activity in situ in the plasma membrane, src-dependent protein phosphorylation in membranes isolated from RSV-CEF has been characterized. These membrane preparations contained high ATPase and phosphoprotein phosphatase activities; but when sufficient concentrations of [gamma-32P]ATP were used, the phosphorylation of pp60src and the phosphorylation of p36 were linear for 1 min or more, and the initial rates of phosphorylation could therefore be determined. In membranes from RSV-CEF pp60src and p36 became phosphorylated predominantly at tyrosine, while in membranes from uninfected cells p36 was phosphorylated at low levels at serine. When membranes from RSV-CEF were preincubated with tumor-bearing rabbit (TBR) serum, the IgG became phosphorylated while the phosphorylation of p36 was inhibited, suggesting that p36 is directly phosphorylated by pp60src. Phosphorylation of pp60src, p36, and TBR-IgG was dependent on growth temperature in membranes from cells infected by a temperature-sensitive mutant, tsNY68, although some dependence on growth temperature was observed even with membranes from wild-type RSV-infected cells. However, at the nonpermissive temperature, tsNY68 pp60src retained 20-40% of its kinase activity, providing supporting for the proposal (B. M. Sefton, T. Hunter, and K. Beemon (1980, J. Virol, 33, 220-229) that transformation may result from a small quantitative change in pp60src activity. The phosphorylation of pp60src and its kinase activity were not coordinately affected by growth temperature or mutations within src, indicating that different factors affect the phosphoacceptor capacity and kinase activity of the protein.
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PMID:pp60src-dependent protein phosphorylation in membranes from Rous sarcoma virus-transformed chicken embryo fibroblasts. 299 19

A cytochemical study of gastric K+-stimulated p-nitrophenylphosphatase (K-NPPase) activity, corresponding to a K+-stimulated phosphoprotein phosphatase of H-K-ATPase system, has been made by a new cytochemical method. Sections of fixed guinea pig gastric mucosa in a mixture of 2% paraformaldehyde and 0.25% glutaraldehyde, were incubated with the incubation medium (1.0 M glycine-0.1 M KOH buffer, pH 9.0, 2.5 ml; 1.1 M KCl, 0.5 ml; 10 mM lead citrate dissolved in 50 mM KOH, 4 ml; levamisole, 6.0 mg; dimethyl sulfoxide, 2.0 ml; 0.1 M p-nitrophenylphosphate (Mg-salt), 1.0 ml; ouabain, 73.0 mg) for 30 min at room temperature. Under a light microscope the specific gastric K-NPPase reaction was distributed only in the parietal cells of the fundic glands. The electron microscopic cytochemistry showed that the gastric K-NPPase activity was localized on the membrane lining the apical surfaces, secretory canaliculi and tubulovesicles. On the other hand, ouabain-sensitive K-NPPase activity (Na-K-ATPase) was demonstrated to localize only in the basolateral membrane of parietal cells with Mayahara's method. These findings support the interrelationships between the apical surface membrane, secretory canalicular membrane and tubulovesicles, and the functional differentiation of the membrane between the secretory membrane and basolateral membrane.
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PMID:Gastric K+-stimulated p-nitrophenylphosphatase cytochemistry. 301 12

Rat stimulated heavy gastric membranes enriched with (H+-K+)-ATPase, a marker for the apical membrane of the parietal cell, displayed a 32P-histone-dephosphorylating activity which appeared to be physically copurified with, but functionally independent of, the ATPase. The protein phosphatase activity was optimal at pH 7.5 and was inhibited by fluoride (50 mM), inorganic phosphate (50 mM), and p-chloromercuribenzoate (0.1 mM), but was insensitive to vanadate (1 mM). The 32P-phosphoproteins in the heavy gastric membranes were also dephosphorylated, apparently by their own membrane-bound phosphatase in the presence of Mg2+ at millimolar concentrations, which is likely to enhance membrane-membrane interaction. Heavy gastric membrane vesicles incubated with Mg2+ (2 mM) exhibited no alterations in K+-dependent ATP-hydrolyzing activity, Cl permeability, and protein and lipid compositions, but irreversibly lost the ATP, K+-dependent H+-pumping activity. Since valinomycin, a K+-specific ionophore, restored the intravesicular acidifying activity and an inhibitor of the protein phosphatase, inorganic phosphate, largely blocked the Mg2+-induced change in the membrane transport function, it is reasonable to propose that the phosphatase action on certain membrane proteins, possibly the putative K+ transporter or regulatory proteins, selectively decreases K+-conductance in the apical membranes of gastric parietal cells.
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PMID:A protein phosphatase associated with rat heavy gastric membranes enriched with (H+-K+)-ATPase influences membrane K+ transport activity. 303 74


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