Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The phospholipase A2 (PLA2) neurotoxin, beta-bungarotoxin (beta-BuTX), presynaptically alters acetylcholine release. We previously found that beta-BuTX inhibits protein phosphorylation in rat brain synaptosomes. This inhibition was not due to the inhibition of ATP synthesis, the action of arachidonic acid (AA) metabolites, or the stimulation of phosphatase activities. A typical PLA2 enzyme from Naja naja atra (N. n. atra) venom also inhibited phosphorylation but with lesser potency than that of beta-BuTX. We now report the effects of beta-BuTX and N. n. atra PLA2 on the activities of protein kinases. Treatments of synaptic plasma membrane or cytosol with N. n. atra PLA2 stimulated the activities of cAMP-dependent kinase, Ca2+/calmodulin-dependent kinase II, and protein kinase C (PKC), whereas beta-BuTX had no effect on these kinases. Calyculin A, a phosphatase-1 and -2A inhibitor, increased the stimulation of phosphorylation by N. n. atra PLA2, indicating that the stimulation is not due to an inhibition of phosphatase activities. The stimulation of PKC by N. n. atra PLA2 appears to be mediated by free fatty acids (FFAs) resulting from phospholipid hydrolysis by PLA2, since (1) treatment of either synaptic plasma membrane or cytosol with N. n. atra PLA2 produced large amounts of FFAs, and (2) AA, an exogenous FFA, stimulated PKC activity to an extent similar to that caused by N. n. atra PLA2. Thus, the mechanisms of action of beta-BuTX and N. n. atra PLA2 appear quite different from each other although both agents inhibit phosphorylation in intact synaptosomes.
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PMID:Differential effects of snake venom phospholipase A2 neurotoxin (beta-bungarotoxin) and enzyme (Naja naja atra) on protein kinases. 893 37

The regulation of the activity of CaMKII by PP-1 and PP-2A, as well as the role of this protein kinase in the phosphorylation of tau protein in forebrain were investigated. The treatment of metabolically active rat brain slices with 1.0 microM okadaic acid (OA) inhibited approximately 65% of PP-2A and had no significant effect on PP-1 in the 16000xg tissue extract. Calyculin A (CL-A), 0.1 microM under the same conditions, inhibited approximately 50% of PP-1 and approximately 20% of PP-2A activities. In contrast, a mixture of OA and CL-A practically completely inhibited both PP-2A and PP-1 activities. The inhibition of the two phosphatase activities or PP-2A alone resulted in an approximately 2-fold increase in CaMKII activity and an approximately 8-fold increase in the phosphorylation of tau at Ser 262/356 in 60 min. Treatment of the brain slices with KN-62, an inhibitor of the autophosphorylation of CaMKII at Thr 286/287, produced approximately 60% inhibition in CaMKII activity and no significant effect on tau phosphorylation at Ser 262/356. The KN-62-treated brain slices when further treated with OA and CL-A did not show any change in CaMKII activity. In vitro, both PP-2A and PP-1 dephosphorylated tau at Ser 262/356 that was phosphorylated with purified CaMKII. These studies suggest (i) that in mammalian forebrain the cytosolic CaMKII activity is regulated mainly by PP-2A, (ii) that CaMKII is the major tau Ser 262/356 kinase in brain, and (iii) that a decrease in PP-2A/PP-1 activities in the brain leads to hyperphosphorylation of tau not only by inhibition of its dephosphorylation but also by promoting the CaMKII activity.
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PMID:Inhibition of PP-2A upregulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser 262/356. 1117 3

The involvement of protein phosphatases in the activation of superoxide (O2-)- generating enzyme in human neutrophils was examined using calyculin A, an inhibitor of protein phosphatase type 1 and 2A. Calyculin A inhibited the phorbol myristate acetate (PMA)- and opsonized zymosan (OZ)-activated O2- generation by human neutrophils. This inhibitory effect of calyculin A on PMA-activated O2- generation was reversed by the addition of KT5926, a specific inhibitor of myosin light chain kinase and Ca2+/calmodulin-dependent protein kinase II. These results suggest that the addition of calyculin A may cause hyperphosphorylation of some protein(s) that plays a crucial role in the PMA-dependent activation of O2- generating enzyme, and that this protein hyperphosphorylation may be evoked by a KT5926-sensitive kinase or its downstream kinase. Whereas two-dimensional analysis involving 32P revealed that calyculin A caused the hyperphosphorylation of many proteins, KT5926 mainly reduced the calyculin A-induced hyperphosphorylation of a 67 kDa protein in activated neutrophils, suggesting that the hyperphosphorylation of the 67 kDa protein might inhibit the PMA-dependent activation of NADPH oxidase. The 67 kDa cytosolic protein was moderately phosphorylated on the addition of PMA. On the other hand, in the absence of calyculin A, KT5926 inhibited both PMA-induced O2- generation and phosphorylation of the 67 kDa protein. Amino acid sequence analysis of peptides derived from the 67 kDa protein revealed that the 67 kDa protein was identical to L-plastin, an actin-bundling protein. We conclude that optimally phosphorylated L-plastin may play some crucial role in the activation of NADPH oxidase.
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PMID:Possible involvement of optimally phosphorylated L-plastin in activation of superoxide-generating NADPH oxidase. 1476 71

Induction of apoptosis by the PP1/PP2A inhibitor calyculin A was inhibited if the CaMKII inhibitor KN-93 was added no later than 10 min after addition of calyculin A. The physiological relevance and mechanism of CaMKII during apoptosis, however, remains largely unclear. Here we show in MDCK and gastric parietal cells that normal transregulation of CaMKII terminates the initial burst of autophosphorylation after only 10 min. The kinetics of CaMKII involved transregulation by PP1, PP2A, PP2B and PKCalpha. Transregulation of CaMKII resulted in two kinetic phases for phosphorylation of the autoactivation site at T286/287. During the initial phase, there was a clear peak of phosphorylation that lasted 10 min. This phase was subsequently followed by a half but constant level of T286/287 phosphorylation. Calyculin A perturbed this transregulation, resulting in a hyperphosphorylated CaMKII. This effect of CA on the kinetics of CaMKII was observed in vivo as well as in vitro using isolated tubulovesicles. Calyculin A-induced hyperphosphorylation of CaMKII appears to be at least one mechanism used by cells to trigger apoptosis. Therefore, stringent limitation of CaMKII autophosphorylation at T286/287 by transregulation and prevention of hyperphosphorylation seems to restrict apoptosis.
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PMID:Stringent time-dependent transregulation of calcium calmodulin kinase II (CaMKII) is implicated in anti-apoptotic control. 1799 39