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)

Immunohistochemical studies prove the most of the neurons of the central nervous system express one or more protein kinase C isoenzymes. However, there are only a few descriptions of the glial localization. In the present study, we detected protein kinase C immunohistochemically in guinea pig sensory neocortex, hippocampus and hippocampal slices following in vitro maintenance. Monoclonal antibodies against types II and III of protein kinase C were used. Consecutive sections were stained with polyclonal anti-glial-fibrillary-acidic protein serum. Scattered astrocytes contained protein kinase C in layers I and VI of the cerebral cortex, in the subcortical white matter, the subiculum, alveus and molecular layer of Ammon's horn, in the hilus and molecular layer of the dentate fascia. Ultrastructurally, immunostaining of glial processes in the neuropil and around blood vessels was observed. Strong staining of the endoplasmic reticulum and nuclear envelope was noted in glial cell bodies. The ultrastructural localization of protein kinase C suggests its participation in receptor-mediated processes, which may influence the shape and function of astrocytes.
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PMID:The astrocytic localization of protein kinase C in the neocortex, hippocampus and in vitro hippocampal slices of the guinea pig. 836

In NIDDM, first-phase insulin release to glucose is (almost) absent. However, in contrast to older studies which suggested that in NIDDM the B-cell is "blind" for glucose, recent evidence indicates that the B-cell is not insensitive for glucose as far as second phase release is concerned. This suggests that the metabolism of glucose is probably not deranged in NIDDM, since glucose leads to insulin release after it has been metabolized. Hyperglycaemia itself has a deleterious effect on insulin release, so-called glucose toxicity. Various mechanisms have been proposed, whereby hyperglycaemia may diminish insulin release: inhibition of Ca2+ mobilization from the endoplasmic reticulum by glucose-6-phosphate, Ca2+ uptake in the ER by glucose and inhibitory effects of protein kinase C. Whatever may prove to be the underlying mechanism(s), glucose toxicity is unlikely to be the only cause of insulin secretory disturbances in NIDDM, since the glucose level would have to be elevated before it could be toxic. Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by both defects in insulin action and insulin secretion. With regard to the defects in insulin release, much research has originated from two (partly) opposing hypotheses, namely the presence of pancreatic B-cell glucose blindness and the hypothesis of pancreatic B-cell glucose toxicity in NIDDM.
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PMID:Defects in insulin secretion in NIDDM: B-cell glucose insensitivity or glucose toxicity? 844 21

Glycoinositol phospholipid (GPI) anchor structures derive from sequentially glycosylated inositol phospholipid precursors assembled in the endoplasmic reticulum. To characterize GPI biosynthesis in nontransformed human lymphocytes and to define the GPI synthetic defect underlying deficient expression of GPI-anchored proteins by paroxysmal nocturnal hemoglobinuria (PNH) cells, putative intracellular GPI intermediates were analyzed following [3H]Man labeling of normal and affected lymphocytes. In unstimulated normal peripheral blood lymphocytes, [3H]Man incorporation into GPIs was minimally detectable but after phytohemagglutinin (PHA), allogeneic cell, or anti-CD3 stimulation, assembly of [3H]Man-labeled GPIs markedly increased. Expression of GPIs by prestimulated quiescent PHA blasts could be efficiently induced by phorbol 12-myristate 13-acetate (PMA) and increased by the Ca2+ ionophore A23187 independently of new protein synthesis. Utilizing allogeneically stimulated cells in conjunction with PMA induction, products deriving from [3H]Man labeling of affected CD48- T and natural killer lymphocyte cell lines from five PNH patients were compared to those deriving from unaffected CD48+ cell lines from the same patients or controls. In contrast to unaffected paired control cells, affected cells of all of the patients exhibited a common abnormality in which they assembled dolichol-phosphoryl-Man but failed to express [3H]Man-containing GPIs. These data indicate that 1) significant GPI production in lymphocytes is dependent on prior stimulation of the cells, 2) exposure of lymphocytes to agents which activate protein kinase C induces GPI synthesis, and 3) in five PNH patients affected lymphocytes are uniformly defective in an early GPI biosynthetic step which undermines expression of GPI mannolipids.
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PMID:Regulation of glycoinositol phospholipid anchor assembly in human lymphocytes. Absent mannolipid synthesis in affected T and natural killer cell lines from paroxysmal nocturnal hemoglobinuria patients. 845

The phorbol ester TPA (phorbol 12-myristate 13-acetate) substitutes for CO2 as an agonist for transforming Trypanosoma cruzi epimastigotes to the metacyclic trypomastigote stage in a starvation medium consisting of phosphate buffered saline + 10 mM proline, 10 mM sodium acetate and 0.035% NaHCO3. Since TPA is thought to stimulate protein kinase C by mimicking the activity of the secondary messenger diacylglycerol, the above result suggested that T. cruzi metacyclogenesis could be activated by a Ca(2+)-dependent protein kinase C signal induction pathway. Accordingly, cytosolic calcium flux ([Ca2+]i) in epimastigotes, activated with 5% CO2 or TPA (10(-7) M), was measured with the Ca2+ molecular probe, fluo-3AM. In addition, [Ca2+]i was measured in cells incubated with putative metacyclogenic agonists (e.g. proline, glutamate, bioamines, ionophores and catecholamines). None of the compounds studies, except for EGTA, affected cytosolic Ca2+ levels. Control assays with 11 microM thapsigargin, which mobilizes noncytoplasmic Ca2+ stores by inhibiting endoplasmic reticulum Ca(2+)-ATPase, validated our fluorometric assay procedure. Although thapsigargin significantly increases cytoplasmic Ca2+ fluorescence, it has no effect on transformation. The protein kinase C inhibitors staurosporine, H-7 and HA 1004 were tested for their effect on T. cruzi metacyclogenesis. Low concentrations of staurosporine and HA 1004 significantly elevated Peru strain transformation while H-7 had no effect on Peru strain metacyclogenesis. Inhibitor H-7 did significantly depress CL transformation. The results indicate that induction of T. cruzi metacyclic trypomastigote formation by CO2 and TPA is not accompanied by changes in cytosolic Ca2+ and do not provide supporting evidence for participation of a protein kinase C-mediated phosphoinositide cascade in metacyclogenesis.
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PMID:Absence of transitory [Ca2+]i flux during early in vitro metacyclogenesis of Trypanosoma cruzi. 846 96

Asphyxia triggers a cascade of cellular biochemical events that lead to temporary alterations in cellular function and/or cell death. Tissue hypoxia and ischemia lead to depolarization of neuronal membranes, alteration in cellular ion homeostasis and changes in energy metabolism. The changes are accompanied by enhanced release and diminished re-uptake of neurotransmitters, including the excitatory amino acid glutamate. Abnormal accumulation of calcium in neurons is produced by several factors, including opening of voltage-sensitive calcium channels, activation of excitatory amino acid-mediated ion channels, diminished pumping of calcium out of neurons, and increased release of free calcium from the endoplasmic reticulum. Elevated intracellular calcium levels appear to kill cells by activation of proteases, lipases, protein kinase C, and generation of free radicals. These factors act synergistically over minutes to hours to produce cellular necrosis. Current research is directed at defining the relative contribution of these steps to cell death and to devising therapeutic strategies to salvage brain tissue.
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PMID:Cellular alterations associated with perinatal asphyxia. 851 12

We previously reported that a hydroquinone-type antioxidant, 2,5-di(tert-butyl)-1,4-hydroquinone (DTBHQ), increases intracellular free Ca2+ concentration ([Ca2+]i), causes degranulation together with a protein kinase C activator, phorbol 12-myristate 13-acetate (TPA), and increases antigen-induced degranulation in rat basophilic leukemia (RBL-2H3) cells. In this study, the effects of five-hydroquinone-type and phenolic antioxidants (2,5-di(tert-amyl)-1,4-hydroquinone [DTAHQ], 2-tert-butyl-1,4-hydroquinone [MTBHQ], 3,5-di(tert-butyl)-4-hydroxytoluene [BHT], 3,5-di(tert-butyl)-4-hydroxyanisole [DTBHA], and 3-tert-butyl-4-hydroxyanisole [MTBHA]) on [ca2+]i and degranulation (beta-hexosaminidase release) were examined and compared with that of DTBHQ. DTAHQ (> or = 3 microM) showed effects similar to those of DTBHQ (10 microM) on [Ca2+]i elevation, induction of degranulation with TPA, and increase of antigen-induced degranulation. BHT (50 microM) and DTBHA (50 microM) caused [Ca2+]i elevation and increased degranulation in the presence of TPA or antigen, but their effects were less than those of DTBHQ and DTAHQ. MTBHQ and MTBHA had no effect on [Ca2+]i and degranulation, even at 50 microM. The degree of Ca2+ response caused by the compounds correlated well with the increase in degranulation, but not with their antioxidant activity estimated with the first oxidation potential. From these results, it is suggested that the increasing effects of six antioxidants on degranulation in the presence of TPA or antigen were dependent on [Ca2+]i increase caused by the compounds, probably through their ability to inhibit endoplasmic reticulum Ca2+-ATPase.
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PMID:Effects of hydroquinone-type and phenolic antioxidants on calcium signals and degranulation of RBL-2H3 cells. 863 92

Biochemical and morphometric approaches were combined to examine whether constitutive secretory transport might be controlled by plasma membrane receptors, as this possibility would have significant physiological implications. Indeed, IgE receptor stimulation in rat basophilic leukemia cells potently increased the rate of transport of soluble pulse-labeled 35S-sulfated glycosaminoglycans from distal Golgi compartments to the cell surface. This effect was largely protein kinase C (PKC)-dependent. Direct activation of PKC also stimulated constitutive transport of glycosaminoglycans, as indicated by the use of agonistic and antagonistic PKC ligands. PKC ligands also had potent, but different, effects on the exocytic transport from distal Golgi compartments to the plasma membrane of a membrane-bound protein (vesicular stomatitis virus glycoprotein), which was slightly stimulated by activators and profoundly suppressed by inhibitors of PKC. Morphological analysis showed impressive changes of the organelles of the secretory pathway in response to IgE receptor stimulation and to direct PKC activation (enhanced number of buds and vesicles originating from the endoplasmic reticulum and Golgi and increase in surface and volume of Golgi compartments), suggestive of an overall activation of exocytic movements. These results show that rapid and large changes in constitutive transport fluxes and in the morphology of the exocytic apparatus can be induced by membrane receptors (as well as by direct PKC stimulation).
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PMID:Regulation of constitutive exocytic transport by membrane receptors. A biochemical and morphometric study. 863 57

Prenylcysteine carboxymethyltransferase, an enzyme involved in the post-translational modification of many signalling proteins, was characterized in insulin-secreting INS-1 cells and normal rat pancreatic islets. The activity of this enzyme was monitored by the methylation of an artificial substrate (a prenylated cysteine analogue) with S-adenosy1[methyl-3H]methionine as methyl donor. More than 95% of the methyltransferase activity was associated with the membranes, and high-salt treatment only partially extracted the enzyme from the membranes. The highest specific activity was in the insulin-granule-enriched 25000 g pellet obtained by differential centrifugation. However, a highly purified insulin-enriched fraction obtained by density centrifugation in Percoll did not exhibit methyltransferase activity. The analyses of marker enzymes for cellular organelles revealed that the methyltransferase was co-localized, with the plasma membrane and probably the endoplasmic reticulum, but not with the mitochondria or lysosomes. Guanosine 5'-[gamma-thio]-triphosphate failed to increase methyltransferase activity directly, although it promotes the methylation of GTP-binding proteins. Mastoparan, Ca2+, cAMP and the protein kinase C activator phorbol 12-myristate 13-acetate did not alter enzyme activity. In addition, methyltransferase activity was not stably modified by stimulation of intact cells using glucose or other agents. However, the carboxymethylation of certain low-molecular-mass G-proteins is increased by glucose stimulation; conversely, treatment of cells with N-acetyl-S-trans,trans-farnesyl-L-cysteine inhibited glucose- and forskolin-induced insulin secretion. These results suggest that the membrane-associated prenylcysteine carboxymethyltransferase may be constitutively active and that the methylation of target proteins in vivo is regulated by the access of these proteins to the methyltransferase, as well as by their active (GTP-liganded) configuration.
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PMID:Characterization of prenylcysteine methyltransferase in insulin-secreting cells. 864 28

The role of mobilization of intracellular Ca2+ in the adrenergic-stimulated cAMP accumulation in rat pinealocytes was investigated with thapsigargin, an agent that inhibits endoplasmic reticulum Ca2+-ATPase. It was found that although thapsigargin alone had no effect on the basal cAMP accumulation, it potentiated the beta-adrenergic-stimulated cAMP response by isoproterenol in a dose-dependent manner. The potentiation was abolished with ethylene glycol bis(beta-aminoethyl ether)-N, N,N',N'-tetraacetic acid-acetoxymethyl ester (EGTA-AM) but persisted in the presence of isobutylmethylxanthine, indicating that thapsigargin enhances cAMP synthesis through elevation of cytosolic intracellular Ca2+ concentration ([Ca2+]i). However, when the pinealocytes were stimulated by norepinephrine, a mixed alpha 1- and beta-adrenergic agonist, thapsigargin dose-dependently inhibited the cAMP response. To investigate this inhibitory effect of thapsigargin, we substituted ionomycin, a [Ca2+]i-elevating agent, and 4 beta-phorbol-12-myristate 13-acetate, an activator of protein kinase C, for the alpha(1)-adrenergic component of the norepinephrine-stimulated response. Although thapsigargin had no effect on the potentiation of the isoproterenol-stimulated cAMP accumulation by ionomycin, it significantly inhibited the potentiation by 4 beta-phorbol-12-myristate 13-acetate. Furthermore, the inhibitory effect of thapsigargin was not affected by cotreatment with EGTA-AM or ionomycin, suggesting that this effect is independent of [Ca2+]i. Similar results were obtained when cyclopiazonic acid was used to inhibit the Ca(2+)-ATPase. Taken together, our results indicate that thapsigargin enhances the beta-adrenergic-stimulated cAMP accumulation through its action in elevating [Ca2+]i but inhibits the potentiation of the beta-adrenergic-stimulated cAMP response by protein kinase C, as a consequence of Ca(2+)-ATPase inhibition.
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PMID:Thapsigargin modulates agonist-stimulated cyclic AMP responses through cytosolic calcium-dependent and -independent mechanisms in rat pinealocytes. 864 50

The role of reversible phosphorylation in histamine-induced Ca2+ oscillations in HeLa cells has been investigated by using various activators and inhibitors of protein kinases and phosphatases. Electroporation was employed to introduce impermeable materials into single cells, which proved to be a useful and convenient tool. Of the kinases examined, cAMP-dependent kinase, protein kinase C, and calmodulin-dependent kinase II (CaMK II), only CaMK II was essential. When added during oscillations, both W-7, a calmodulin antagonist, and KN-62, a specific CaMK II inhibitor, caused one large Ca2+ spike before halting the process. Introduction of the Ca2+/calmodulin-independent catalytic domain of CaMK II into the cells forestalled their response to histamine. These results show that intracellular Ca2+ cannot oscillate when CaMK II is locked in either the inactive or the stimulated state. External Ca2+ electroporated into cells preloaded with the catalytic domains was quickly removed (but not when the cells were pretreated with the endoplasmic reticulum Ca(2+)-ATPase inhibitor, tapsigargin), indicating that the ATP-driven Ca2+ pump was somehow activated by CaMK II. Protein phosphatase inhibitors calyculin A and okadaic acid abolished ongoing oscillations and, when added at low concentrations, prolonged the interspike interval. Immunoprecipitation experiments with 32P(i)-labeled cells provided the first evidence that inositol 1,4,5-trisphosphate receptor (IP3R) was phosphorylated by CaMK II in vivo. The extent of phosphorylation was increased in the presence of histamine, significantly enhanced by calyculin A, and greatly reduced by W-7. Our observations are consistent with the concept that repetitive phosphorylation-dephosphorylation cycles regulating IP3R and Ca2+ pumps are a controlling factor for sustained Ca2+ oscillations in HeLa, and possibly other, cells.
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PMID:Reversible phosphorylation as a controlling factor for sustaining calcium oscillations in HeLa cells: Involvement of calmodulin-dependent kinase II and a calyculin A-inhibitable phosphatase. 867 50


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