Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies in the past several years have provided direct evidence that protein phosphorylation is involved in the regulation of neuronal function. Electrophysiological experiments have demonstrated that three distinct classes of protein kinases, i.e., cyclic AMP-dependent protein kinase, protein kinase C, and CaM kinase II, modulate physiological processes in neurons. Cyclic AMP-dependent protein kinase and kinase C have been shown to modify potassium and calcium channels, and CaM kinase II has been shown to enhance neurotransmitter release. A large number of substrates for these protein kinases have been found in neurons. In some cases (e.g., tyrosine hydroxylase, acetylcholine receptor, sodium channel) these proteins have a known function, whereas most of these proteins (e.g., synapsin I) had no known function when they were first identified as phosphoproteins. In the case of synapsin I, evidence now suggests that it regulates neurotransmitter release. These studies of synapsin I suggest that the characterization of previously unknown neuronal phosphoproteins will lead to the elucidation of previously unknown regulatory processes in neurons.
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PMID:Protein phosphorylation and neuronal function. 258 86

The transport of cholesterol to the inner mitochondrial membrane, a key step in steroidogenesis, is subject to hormonal modulation that, at least in part, could be mediated by protein phosphorylation. This step is stimulated by sterol carrier protein 2 (SCP2) and Ca2+. To explore whether SCP2 itself is a potential control point for regulation by Ca2+-dependent phosphorylation we investigated whether highly purified SCP2 could serve as a substrate for major type Ca2+ and non-Ca2+-dependent protein kinases. Phosphorylation by calmodulin protein kinase II (CaM-PK II), myosin light chain kinase (MLCK), cAMP-dependent kinase (PKA) and protein kinase C (PKC) was monitored under optimal conditions for each enzyme. PKA, CaM-PK II and MLCK catalyzed the radiolabeling of histone 2A, synapsin I and myosin light chain (MLC), known substrates for these kinases, respectively, yet no phosphate transfer to SCP2 was observed. In contrast, PKC from two different sources (rat and calf brain) effectively catalyzed the phosphorylation of the highly purified SCP2. The phosphorylation of SCP2 depended on the addition of Ca2+ and phospholipids and was completely blocked by Polymyxin B, a PKC inhibitor. PKC catalyzed phosphorylation of SCP2 displayed a similar dependence on the concentration of ATP. Lineweaver Burk plots of the data indicate Km values for ATP of approximately 6 microM for the phosphorylation of SCP2. Our results, which have revealed for the first time that SCP2 is a substrate for PKC, are consistent with the possibilities that the control of steroidogenesis by tropic hormones and by PKC activation are mediated, at least in part, by the phosphorylation/dephosphorylation of SCP2.
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PMID:Protein kinase C catalyzed phosphorylation of sterol carrier protein 2. 273 66

Aspects of protein phosphorylation related to events occurring during synaptic transmission were briefly reviewed. High resolution two-dimensional electrophoresis was used to study protein phosphorylation catalysed by protein kinase C in a fraction from rat brain enriched in synaptosomes. Incubation of 32P-labelled synaptosomes with 4 beta-phorbol 12 beta-myristate 13 alpha-acetate resulted in an increase in the phosphorylation of a 45 K polypeptide (generally known as B-50) and an 82 K polypeptide; other major phosphoproteins in the preparation were unaffected by this treatment. It appears therefore that the 45 K and 82 K polypeptides are the only significant substrates for protein kinase C in synaptosomes. Depolarisation of labelled synaptosomes by high K+ increased the phosphorylation of the 82 K polypeptide, synapsin I and several unknown phosphoproteins. Incubation of labelled synaptosomes with the cholinergic agonist carbachol resulted in a modest, but statistically significant, increase in the phosphorylation of the 45 K (B-50) and 82 K polypeptides. This effect was blocked by atropine. The results are discussed in relation to a possible role for the B-50 phosphoprotein in regulating the resynthesis of polyphosphoinositides following cholinergic stimulation.
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PMID:Protein phosphorylation and synaptic transmission: receptor mediated modulation of protein kinase C in a rat brain fraction enriched in synaptosomes. 303 26

When intact rat brain synaptosomes are depolarized there is a significant increase in the phosphorylation of many proteins, and a rapid dephosphorylation of a 96,000 dalton protein termed P96. The mechanisms governing dephosphorylation are shown to be distinct from the mechanisms leading to increased phosphorylation of proteins such as synapsin I. Depolarization-dependent P96 dephosphorylation was found to be rapid (preceding the phosphorylation of synapsin I) and fully reversible, and required both depolarization and calcium entry. The phosphorylation of P96 was specifically increased by fluphenazine and by the calcium channel agonist (BAY K 8644) and antagonist (verapamil) by unknown mechanisms. Phosphorylation was also increased in the presence of dibutyryl cAMP indicating some role for cAMP-dependent protein kinase in P96 labeling. Preliminary evidence also raises the possibility of a role for protein kinase C. The characteristics of this unique synaptosomal protein suggest that it may play an important role in nerve terminal function.
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PMID:Regulation of the phosphorylation and dephosphorylation of a 96,000 dalton phosphoprotein (P96) in intact synaptosomes. 343 56

The phospholipase A2 neurotoxin, beta-bungarotoxin, presynaptically blocks acetylcholine release. Its mechanism of action is unknown; however, our previous studies suggest that it inhibits phosphorylation of synaptosomal proteins, which might be expected to decrease neurotransmitter release. In our present study, we found that 1 nM beta-BuTX blocked phorbol ester-stimulated phosphorylation of GAP-43, MARCKS and synapsin I without affecting their basal phosphorylation. In contrast, a 1 nM concentration of the non-neurotoxic enzyme. Naja naja atra phospholipase A2 did not affect the phorbol ester-stimulated phosphorylation of these proteins but increased the basal phosphorylation of GAP-43 and MARCKS. Although it has been suggested that cytosolic calmodulin is increased by phosphorylation of the protein kinase C substrates, GAP-43 and MARCKS, we found no change in calmodulin levels by phorbol ester or beta-bungarotoxin. The stimulation of phosphorylation by Naja naja atra phospholipase A2 may be due to products liberated as a result of its phospholipase A2 activity. In contrast, the inhibition of phosphorylation by beta-bungarotoxin appears to be due to an action which may be unrelated its relatively weak phospholipase A2 activity. Inhibition of phosphorylation by beta-bungarotoxin is a possible mechanism by which it could block acetylcholine release. Furthermore, beta-bungarotoxin may be a useful tool to study the physiological role of phosphorylation of synaptosomal proteins in neurotransmitter release.
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PMID:beta-Bungarotoxin blocks phorbol ester-stimulated phosphorylation of MARCKS, GAP-43 and synapsin I in rat brain synaptosomes. 767 66

Both Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) and protein kinase C (PKC) have been implicated as possible candidates for contributing to the induction of long-term potentiation (LTP) in the hippocampus. The induction of LTP in the CA1 region of the hippocampus, an event which requires postsynaptic Ca2+ influx through NMDA-type glutamate receptors, is blocked by calmodulin antagonists and inhibitors of CaM kinase II and PKC. In the present study, we describe the activation characteristics of CaM kinase II and PKC through the stimulation of glutamate receptors and regulation of the phosphorylation of substrates for CaM kinase II in the hippocampus. In cultured rat hippocampal neurons, glutamate elevated the Ca(2+)-independent activity of CaM kinase II through autophosphorylation, and this response was blocked by specific antagonists of the NMDA receptor. In addition, glutamate stimulated the translocation of PKC from the cytosol to the membrane fraction through the metabotropic glutamate receptor. In the experiments with 32P-labeled cells, the phosphorylation of microtubule-associated protein 2 (MAP2) and synapsin I was stimulated by the exposure to glutamate. Finally, we demonstrated that high, but not low, frequency stimulation applied to two groups of CA1 afferents in the slices resulted in the induction of LTP with concomitant long-lasting increases in the Ca(2+)-independent and total CaM kinase II activities as well as the autophosphorylation. It could be blocked by preincubation of the slices with NMDA-receptor antagonist. These results suggest that glutamate can activate CaM kinase II through NMDA receptors in the induction of LTP and in turn stimulates the phosphorylation of target proteins such as MAP2 and synapsin I.
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PMID:[The role of Ca2+/calmodulin-dependent protein kinase II in the cellular signal transduction]. 828 67

The cytoplasmic domain of synaptotagmin (a synaptic vesicle-specific protein) has a high degree of homology with the Ca(2+)-phospholipid binding domain of protein kinase C. The Ca(2+)-phospholipid binding activity of synaptotagmin has been implicated in the docking and fusion of synaptic vesicles with the presynaptic membrane during Ca(2+)-induced exocytosis. The protein sequence contains potential phosphorylation sites for various protein kinases which could modulate its binding activity. At present there is no clear evidence that the protein is endogenously phosphorylated in intact vesicles. Here it is reported that phospho-synaptotagmin was immunoprecipitated from endogenously phosphorylated synaptic vesicles. The conditions used indicate that synaptotagmin, as synapsin I, is phosphorylated by Ca2+/calmodulin-dependent protein kinase II.
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PMID:Synaptotagmin is endogenously phosphorylated by Ca2+/calmodulin protein kinase II in synaptic vesicles. 838 69

Peripheral nerve regeneration comprises the formation of axonal sprouts, their outgrowth as regenerating axons and the reinnervation of original targets. This review focuses on the morphological features of axonal sprouts at the node of Ranvier and their subsequent outgrowth guided by Schwann cells or by Schwann cell basal laminae. Adhesion molecules such as N-CAM, L1 and N-cadherin are involved in the axon-to-axon and axon-to-Schwann cell attachment, and it is suggested that integrins such as alpha 1 beta 1 and alpha 6 beta 1 mediate the attachment between axons and Schwann cell basal laminae. The presence of synaptic vesicle-associated proteins such as synaptophysin, synaptotagmin and synapsin I in the growth cones of regenerating axons indicates the possibility that exocytotic fusion of vesicles with the surface axolemma supplies the membranous components for the extension of regenerating axons. Almost all the subtypes of protein kinase C have been localized in growth cones both in vivo and in vitro. Protein kinase C and GAP-43 are implicated to be involved in at least some part of the adhesion of growth cones to the substrate and their growth activity. The significance of tyrosine kinase in growth cones is emphasized. Tyrosine kinase plays an important role in intracellular signal transduction of the growth of regenerating axons mediated by both nerve trophic factors and adhesion molecules. Growth factors such as NGF, BDNF, CNTF and bFGF are also discussed mainly in terms of the influence of Schwann cells on regenerating axons.
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PMID:Peripheral nerve regeneration. 882 47

The snake venom phospholipase A2 neurotoxin, beta-bungarotoxin, acts presynaptically to alter acetylcholine release in both the peripheral and central nervous systems. In investigating the mechanism of this action, we found that beta-bungarotoxin inhibited phosphorylation of synapsin I, GAP-43 and MARCKS in rat brain synaptosomes. This inhibition was not due to the inhibition of ATP synthesis, action of arachidonic acid metabolites, or stimulation of phosphatase activities. Furthermore, the activities of Ca2+/calmodulin-kinase II, cAMP-kinase and protein kinase C were not altered by beta-bungarotoxin in either synaptic plasma membranes or cytosol. When synaptic plasma membranes were treated with beta-bungarotoxin, MARCKS phosphorylation was inhibited, and this inhibition was overcome by the addition of exogenous protein kinase C. These results suggest that the interaction between MARCKS and endogenous protein kinase C is altered by beta-bungarotoxin. In contrast, Naja naja atra phospholipase A2, a typical phospholipase A2 enzyme, had effects on phosphorylation which were different from those of beta-bungarotoxin: (1) inhibition of phosphorylation of synapsin I in intact synaptosomes was less potent than that by beta-bungarotoxin; (2) it stimulated basal phosphorylation of GAP-43 and MARCKS; and (3) it increased the activity of protein kinase C. The inhibition of synapsin I phosphorylation by N. n. atra phospholipase A2 in intact synaptosomes may be due to the inhibition of ATP synthesis. The stimulation of GAP-43 and MARCKS by N. n. atra phospholipase A2 can be explained by the production of arachidonic acid, which stimulated protein kinase C activity to a similar extent as that caused by N. n. atra phospholipase A2. Thus, the mechanism of action of beta-bungarotoxin appears to be quite different from that of a phospholipase A2 enzyme, suggesting that phospholipase A2 activity of beta-bungarotoxin may not be essential for its action. beta-Bungarotoxin may be a useful tool to study the physiological role of phosphorylation of synaptosomal proteins in neurotransmitter release.
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PMID:Mechanism of action of beta-bungarotoxin, a presynaptically acting phospholipase A2 neurotoxin: its effect on protein phosphorylation in rat brain synaptosomes. 902 77

Repeated, intermittent treatment of rats with amphetamine followed by a withdrawal period leads to an enhancement in amphetamine-induced dopamine release. We previously reported an increased stoichiometry of site 3-phospho-synapsin I and increased levels of phospho-Ser41-neuromodulin in striatum after repeated amphetamine. In this study, we examined whether the enhanced amphetamine-induced dopamine release and increased levels of these phosphoproteins would be detected in synaptosomes from rats pretreated and withdrawn from repeated amphetamine. Enhanced amphetamine-induced dopamine release was detected in striatal synaptosomes from rats treated with repeated amphetamine compared with controls. The enhanced dopamine release was Ca++ dependent. State-specific antibodies were used to measure the levels of site 3-phospho-synapsin I, phosphorylated by CaM kinase II, and phospho-Ser41-neuromodulin, phosphorylated by protein kinase C, in incubated striatal S1 fractions and synaptosomes. The levels of site 3-phospho-synapsin I and phospho-Ser41-neuromodulin were increased by 40% and 30%, respectively, in amphetamine-pretreated rats compared with controls. Total neuromodulin and synapsin I was not altered. There was a significant 26% increase in CaM kinase II activity in the synaptosomes from amphetamine-pretreated rats but no change in content. No change in protein kinase C activity or content of the alpha-isozyme was detected after repeated amphetamine. Our results demonstrate that the enhanced amphetamine-induced dopamine release and occurring after repeated amphetamine can be detected in synaptosome preparations. Repeated amphetamine leads to alterations in phosphorylation/dephosphorylation activities that can be detected in the incubated synaptosomes. Because the enhanced amphetamine-induced dopamine release after repeated amphetamine appears to be Ca++ sensitive, it is possible that the altered phosphorylation systems, and perhaps site 3-phospho-synapsin I and phospho-Ser41-neuromodulin, play a role in the enhanced dopamine release.
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PMID:Enhanced dopamine release and phosphorylation of synapsin I and neuromodulin in striatal synaptosomes after repeated amphetamine. 940 20


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