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)

Neuropathic pain following nerve injury is thought to involve central nervous system Ca(2+)-mediated neuronal plastic changes. This study provides evidence that induction and/or maintenance of post-injury neuropathic pain behaviors in the rat is associated with increases in membrane-bound protein kinase C (PKC), a Ca(2+)-dependent process known to mediate central nervous system neuronal plasticity. In addition, spinal cord administration of GM1 ganglioside, an intracellular inhibitor of PKC translocation/activation, reverses both increased levels of membrane-bound PKC and pain-related behaviors. Thus, persistent post-injury neuropathic pain may be mediated by the initiation of excitatory neuropathological processes resulting from an increase in membrane-bound PKC.
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PMID:Pain-related increases in spinal cord membrane-bound protein kinase C following peripheral nerve injury. 139 64

In previous studies (Morrison et al., 1990), we showed that ganglioside (GM1) modulation of CD4 was associated with activation of phospholipase C and increased production of inositol triphosphate, but not with activation of protein kinase C. These results demonstrated a unique signal transduction pathway related to GM1 modulation of CD4 on T cells and raised the question as to whether intracellular Ca2+ levels and related protein kinases would be affected by GM1-induced signalling. We now show that GM1 modulation of CD4 from human T cells corresponds to decreased cellular Ca2+ without significant changes in cellular protein phosphorylation. In the course of this study we discovered that T cells challenged with GM1 exhibited new proteins in their surrounding media. Fractionation of cellular and supernatant proteins show that cells treated with GM1 released proteins with an approximate molecular weight (Mr) of 49,000. This was exclusive of GM1 protein association and GM1-induced protein phosphorylation. Immunoblots demonstrated the presence of CD4 in GM1-treated cell supernatants. Western immunoblots using anti-CD4 antibodies detected a lower Mr form (49,000) of CD4 in the supernatants of GM1-treated cells. These studies further define the unique nature of GM1 signalling relating to modulation of CD4 and demonstrate that the fate of GM1 modulated CD4, in part, involves protein shedding.
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PMID:Ganglioside (GM1)-treated T cells shed CD4. 176 2

Ganglioside (GM1) treatment of CD4+ human CEM lymphoma cells stimulated transient phosphoinositide (PI) breakdown, production of inositol phosphates (IP), protein phosphorylation and rapid decrease of CD4 surface expression. A comparison between the actions of GM1 and other agents that affect these signal transduction pathways demonstrated a distinct mechanism for GM1-induced decrease of CD4. GM1 stimulated both phospholipase C activity and protein phosphorylation but had no effect on either cellular cAMP levels or tyrosine kinase activity. Phorbol myristate acetate (PMA) stimulated protein phosphorylation and caused a significant decrease in surface display of CD4. Both of these processes were blocked by pretreating cells with the protein kinase C (PKC) inhibitor H7. These results demonstrate that GM1 stimulates PI turnover and induces a rapid decrease of CD4 surface expression by processes that do not activate adenylate cyclase or tyrosine kinase. They further demonstrate that the mechanism for GM1-induced decrease of CD4 is distinct from the CD4 internalization processes mediated by PKC activity.
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PMID:Transmembrane signalling associated with ganglioside-induced CD4 modulation. 217 87

Complete obstruction of the maternal blood flow to fetal rats at 20 days of gestation for a period of 10 min causes a significant shift of approximately 22% in protein kinase C (PKC) activity from a cytosolic to a membrane-bound form in the fetal brain. This translocation can be entirely reversed without losses in activity by a single intraperitoneal injection into the gravid rat of either a mixture of disialo- and trisialoganglioside [polysialoganglioside (PSG)] or by GM1 (50 mg/kg of body weight) given 3 h before onset of the ischemic episode. Cessation of blood flow for 15 min followed by a reperfusion period of 24 h results in a 47% loss in total PKC activity. This down-regulation can be almost entirely prevented upon intraperitoneal administration of GM1 3 h before, but also during and even 90 min after the onset of ischemia. The PSG mixture is also effective, particularly when given 3 h before the insult. Down-regulation of PKC is accompanied by an increase in a Ca2(+)-phosphatidylserine-independent kinase [protein kinase M (PKM)] activity, which rises from 30 pmol/min/mg of protein in control animals to a maximal value of 83.1 pmol/min/mg of protein after 15 min of ischemia and 6 h of reperfusion. By 24 h, PKM activity is 46.8 pmol/min/mg of protein. Administration of GM1 blocks completely the appearance of PKM, a result suggesting that PKC down-regulation and PKM activity elevation are intimately associated events and that both are regulated by GM1 ganglioside.
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PMID:Gangliosides prevent ischemia-induced down-regulation of protein kinase C in fetal rat brain. 223 Aug 13

Gangliosides inhibit the phosphorylation of both small and large rat myelin basic proteins (SMBP, LMBP) by an endogenous phospholipid-sensitive Ca2+-dependent protein kinase (C-kinase). Using a rat brain myelin preparation in an in vitro phosphorylation assay system, we determined the inhibition constants (IC50's) of the gangliosides GM1, GD1a, GD1b, and GT1b to be approximately 160 microM, 65 microM, 65 microM, and 40 microM, respectively. Asialoganglioside GA1, ceramide, and N-acetylneuraminic acid (NANA, sialic acid) failed to produce similar inhibition, suggesting that both the lipid and the sialic acid moieties are necessary, but neither alone is sufficient to produce inhibition. The results indicate that gangliosides may regulate protein kinase C activities in the nervous system.
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PMID:Gangliosides inhibit phospholipid-sensitive Ca2+-dependent kinase phosphorylation of rat myelin basic proteins. 242 Oct 6

The activity of protein kinase C (Ca2+/phospholipid-dependent enzyme) in the presence of phosphatidylserine and its physiological regulator, diacylglycerol, could be suppressed by a mixture of brain gangliosides. Half-maximal inhibition was observed at 30 microM and was nearly complete at 100 microM. Inhibition was observed at all concentrations of Ca2+ between 10(-8) and 10(-4) M. Inhibition of protein kinase C activity could not be reversed by increasing the concentration of diacylglycerol or the substrate, histone. Inhibition was also observed when myelin basic protein or a synthetic myelin basic protein peptide was used as substrate. Among the individual gangliosides, the rank order of potency was GT1b greater than GD1a = GD1b greater than GM3 = GM1. Our results suggest that gangliosides may regulate the responsiveness of protein kinase C to diacylglycerol.
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PMID:Regulation of protein kinase C activity by gangliosides. 243 84

Gangliosides have profound effects on the phosphorylation of several proteins in myelin. Addition of polysialogangliosides to purified guinea pig brain myelin enhanced the endogenous phosphorylation of a 62-kDa phosphoprotein, but completely inhibited the phosphorylation of myelin basic protein (MBP) (18.5 kDa). The ganglioside-stimulated phosphorylation of the 62-kDa protein was dose-dependent and -specific. Asialo-GM1, ceramide trihexosides, N-acetylneuraminic acid, or colominic acid alone could not mimic this effect, suggesting that the activation process requires both the hydrophobic head group and the anionic character of the gangliosides. Studies on the time course of this reaction revealed that it was a rapid and reversible process and was affected only very slightly by Ca2+. Thus, the stimulatory effect of gangliosides may not involve Ca2+-gangliosides complexes or proteolysis, but may be mediated through an activation of a ganglioside-dependent protein kinase or due to substrate protein-glycolipid interaction. Modulation of the phosphorylation of MBP by gangliosides varies with the states of phosphorylation of this protein. Prior addition of ganglioside to myelin inhibited the phosphorylation of MBP. However, addition of gangliosides to myelin subsequent to maximal phosphorylation of MBP retarded the dephosphorylation of this protein. Phosphorylation of isolated MBP by protein kinase C was stimulated by gangliosides, provided phosphatidylserine was present. In contrast, the glycolipid inhibited the phosphorylation of a unique site catalyzed by cAMP-dependent protein kinase. This site was distinct from those phosphorylated by protein kinase C and was also sensitive to chymotryptic cleavage. Although the exact physiological significance of protein phosphorylation in myelin has yet to be established, gangliosides may play an important role in the modulation of this reversible post-translational modification mechanism.
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PMID:Ganglioside-modulated protein phosphorylation in myelin. 243 83

In quiescent Swiss 3T3 fibroblasts, the B subunit of cholera toxin, a protein which binds specifically to ganglioside GM1 on the cell surface, stimulates DNA synthesis and potentiates the effects of several other growth factors such as insulin, epidermal growth factor, bombesin, and even unfractionated serum. In contrast to its synergistic effect with other known growth factors, the B subunit markedly inhibited DNA synthesis induced by the phorbol ester, 12-O-tetradecanoyl-phorbol 13-acetate (TPA). The inhibitory effect of the B subunit was observed even in the presence of insulin, which greatly potentiates the mitogenic response to TPA or the B subunit. In contrast to the effect of the B subunit, calcium ionophores and cholera toxin stimulated DNA synthesis induced by TPA. The antagonism between the B subunit and TPA is not simply due to their abilities to modify their mutual binding sites or known effector systems. TPA did not block the early rise in cytosolic free calcium in response to the B subunit, and conversely, the B subunit did not modify the ability of TPA to activate protein kinase C. However, in protein kinase C-deficient cells, the antagonistic effect between TPA and the B subunit was abolished. In addition, there was no indication for the involvement of a pertussis toxin-sensitive G protein in the antagonism. Maximum inhibition was found when the B subunit was added 2 h after the addition of TPA. Significant inhibition was still evident when the time of addition of the B subunit was delayed until 6 h after the addition of TPA. This suggests that the cross-talk between signal transduction induced through endogenous gangliosides and protein kinase C is a late step in mitogenesis.
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PMID:Inhibition of protein kinase C-dependent cellular proliferation by interaction of endogenous ganglioside GM1 with the B subunit of cholera toxin. 267 35

A prolonged (at least 2-4 hr) elevation of [Ca2+]i accompanies early T cell activation by TCR/CD3-specific ligands. Ca2+ is generally thought to be an essential second messenger for early activation, but the precise molecular events contingent upon the Ca2+ signal remain to be determined. The Ca2+ signal can be separated into an early transient peak due to InsP3-released Ca2+ from intracellular stores, and a sustained plateau due to altered transmembrane Ca2+ flux. Patch clamp studies have identified an InsP3-activated, Ca2+ permeable channel in the plasma membrane of T lymphocytes that may be responsible for the sustained elevation of [Ca2+]i during continuous TCR/CD3 occupancy. The Ca2+ signal can be further resolved at the level of the single cell into a series of repetitive oscillations between peak and trough levels with a period of 16-20 s. The oscillations may be part of a frequency-encoded signaling system. Several nonlinear internal feedback controls may contribute to the periodic nature of the Ca2+ signal: PKC-mediated phosphorylation of the CD3 gamma subunit, which is a feedback inhibitor of TCR/CD3 function; amplification of Ca2+ release from endoplasmic reticulum by a highly cooperative step in the opening of Ca2+ channels by InsP3, and Ca2+-dependent feedback enhancement of PLC function; autoregulatory negative feedback on Ca2+ influx by Ca2+, both by a direct effect on the plasma membrane Ca2+ channel and by induction of membrane hyperpolarization secondary to Ca2+-activated K+ efflux. In addition, several other internal feedback controls on TCR/CD3 function, by CD4-induced tyrosine-specific phosphorylation of the CD3 zeta subunit, or on the Ca2+ signal, by extracellular Cl- or by GM1 gangliosides, are also postulated. The question of whether a G protein couples TCR/CD3 to PI hydrolysis and to Ca2+ mobilization is unresolved, although some indirect evidence for the involvement of GTP binding proteins in T cell activation has recently been obtained with cholera toxin. There is also preliminary evidence that TCR/CD3 may structurally conform to G protein coupled receptors, i.e., having a core structure of seven alpha helical transmembrane spanning segments, a ligand recognition site, loci for regulatory phosphorylation, and a putative nucleotide binding site.
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PMID:Calcium and T lymphocyte activation. 267 93

Exposure of HL-60 leukemia cells to either 12-O-tetradecanoylphorbol-13-acetate (TPA), dimethylsulfoxide (DMSO), exogenous gangliosides GM3, GM1, or bovine brain ganglioside mixture (BBG) resulted in a marked inhibition of the growth of cells. The order of the inhibitory potency was TPA greater than GM3 greater than DMSO greater than BBG greater than GM1. In contrast, sulfatides were without effect on cellular replication. Treatment of HL-60 cells with TPA or GM3 induced differentiation along the monocyte/macrophage lineage, while treatment with DMSO induced maturation along the granulocytic pathway. These effects were accompanied by more than a twofold increase in protein kinase C (PKC) activity. In contrast, treatment with GM1, BBG, or sulfatides caused only a relatively small increase in PKC activity. The activity of CMP-N-acetylneuraminic acid:lactosylceramide sialyltransferase (ST1), a key enzyme for membrane gangliosides synthesis, in HL-60 cells was also influenced by the exposure to TPA, GM3, DMSO, GM1, or sulfatides. The inducers of differentiation, TPA and DMSO, caused an increase in ST1 activity, whereas GM3, which also induced cellular differentiation, inhibited ST1 activity, perhaps through the action of end-product inhibition. The non-inducers of differentiation, GM1 and sulfatides, also increased the activity of ST1, but to a much lesser extent. The findings suggest that the direct or indirect modulation of PKC activity by some of these agents may be involved, at least in part, in the regulation of cellular growth and differentiation. Furthermore, it is conceivable that differences in PKC activity may be responsible for the changes in ST1 activity associated with cell differentiation and proliferation.
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PMID:Effects of inducers of differentiation on protein kinase C and CMP-N-acetylneuraminic acid:lactosylceramide sialyltransferase activities of HL-60 leukemia cells. 271 23


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