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)

Activation of protein kinase C (PKC) is regulated by dual second messengers; diacylglycerol (DG) produced by receptor mediated hydrolysis of phosphatidylinositol and Ca2+ which is released by inositol 1,4,5-triphosphate (IP3) from intracellular stores in the endoplasmic reticulum. In the mammalian central nervous system, available evidence suggests that PKC plays a prominent role in the processing of neuronal signals and in the short-term or long-term modulation of synaptic transmission. This enzyme is a member of a family consisting of at least eight subspecies, alpha, beta I, beta II, gamma, delta, epsilon, zeta and eta. The homologous structure of each subspecies makes difficult resolution of the enzymological properties of the enzyme. The distinct functional roles of PKC subspecies in mammalian tissues have been elucidated by defining the localization of each subspecies. We identified alpha-, beta I-, beta II- and gamma-PKC subspecies in the rat brain by in situ hybridization and by light and electron microscopic immunohistochemistry, using antibodies specific for each subspecies. Most immunoreactions of the alpha, beta I, beta II and gamma subspecies were evident in neurons and there were few, if any, in glial cells. In this article, we summarize known cellular and subcellular localizations of PKC subspecies in mammalian CNS and some aspects of current studies in neuronal functions regulated by this enzyme are discussed.
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PMID:Localization of subspecies of protein kinase C in the mammalian central nervous system. 130 31

There is evidence that the rab class of low molecular weight GTP-binding proteins is involved in vesicular transfer from endoplasmic reticulum to Golgi and between Golgi cisternae. To determine whether similar proteins play a role in regulated exocytosis, the effects of synthetic peptides derived from low molecular weight GTP-binding proteins on catecholamine secretion from digitonin-permeabilized chromaffin cells were investigated. The synthetic peptides represent the putative effector-binding domains of the rab, ras and ral classes of low molecular weight GTP-binding proteins and correspond to ras(33-48). Two rab peptides but neither a ras nor a ral peptide enhanced Ca(2+)-dependent secretion by approximately 30%. Maximal secretion in response to Ca2+ was increased. The enhancement was not blocked by the pseudosubstrate inhibitor of protein kinase C, PKC(19-31), thus indicating that activation of protein kinase C was not responsible for the enhancement of secretion. Similarly a rab peptide but neither a ras nor a ral peptide enhanced GppNHp-induced secretion 30-70%. The peptides had little or no effect in the absence of Ca2+ or GppNHp. The data are consistent with a protein of the rab class playing a role in regulated exocytosis.
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PMID:Synthetic peptides of the effector-binding domain of rab enhance secretion from digitonin-permeabilized chromaffin cells. 132 49

Calcium uptake by the endoplasmic reticulum (ER) is important for cellular calcium homeostasis, yet its regulation in nonmuscle cells is poorly understood. We reported that Ca2+ uptake by a light fraction of canine renal cortical ER (LER) is stimulated by protein kinase C in vitro. Here we describe conditions in vivo that stimulate renal cortical LER Ca2+ uptake. Thirty minutes after contralateral nephrectomy in the dog, 45Ca2+ uptake into renal cortical LER was increased 42% above control LER. There was no difference in LER Ca2+ uptake 24 hours after uninephrectomy. Acute denervation did not reproduce the increase in LER 45Ca2+ uptake seen at 30 minutes after uninephrectomy, nor did prior thyroparathyroidectomy abolish it. Forty-eight hours after thyroparathyroidectomy, 45Ca2+ uptake activity into renal cortical LER was decreased approximately sevenfold. In a proximal tubular cell line (LLC-PK1), 30-minute incubation with 12-O-tetradecanoylphorbol-13-acetate doubled 45Ca2+ uptake into a nonmitochondrial pool. Pretreatment with epidermal growth factor halved ER Ca2+ uptake, whereas insulin-like growth factor and growth hormone, alone or in combination, had no effect. Our data suggest that Ca2+ uptake into renal cortical ER is stimulated acutely during compensatory renal growth, perhaps through protein kinase C, and is stimulated chronically by parathyroid hormone.
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PMID:Ca2+ uptake by endoplasmic reticulum of renal cortex. II. Effects of uninephrectomy and parathyroidectomy. 139 76

Cytosolic free Ca2+ rises in pancreatic beta-cells in response to glucose stimulation and is part of the coupling to insulin secretion. This study evaluates a possible role for cytosolic long chain acyl-CoA esters in modulating Ca2+ handling by clonal beta-cells (HIT). Intact cells incubated with 20 microM free palmitic acid exhibited a 40% decrease in basal cytosolic free Ca2+. In contrast, acyl-CoA esters, up to a chain length of 16, but not the corresponding fatty acids, significantly lowered the Ca2+ set point maintained by cells permeabilized with saponin. The maximum response to the various acyl-CoA esters increased with increasing chain length, with no differences in the half-maximally effective concentration of 0.5 microM. Long chain acyl-CoA esters caused a 40-50% increase in 45Ca2+ influx into a non-mitochondrial pool in the permeabilized HIT cells, consistent with a stimulatory effect on the endoplasmic reticulum Ca(2+)-ATPase activity, but did not affect inositol 1,4,5-trisphosphate-induced Ca(2+)-efflux. Thapsigargin, an inhibitor of endoplasmic reticulum Ca(2+)-ATPase activity, blocked the decrease in the Ca2+ set point caused by acyl-CoA esters. The ability of acyl-CoA esters to lower the Ca2+ set point depended on the ATP/ADP ratio (or free ADP); the Ca2+ set point was lowered by 36 +/- 3.6% at an ATP/ADP ratio of 90 and by 14 +/- 1.9% at an ATP/ADP ratio of 7. Depletion of cellular protein kinase C did not prevent the acyl-CoA-induced lowering of the Ca2+ set point. These findings suggest that the increases in long chain acyl-CoA esters may play a role in restoring cytosolic free Ca2+ through activation of Ca(2+)-ATPases.
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PMID:Acyl-CoA esters modulate intracellular Ca2+ handling by permeabilized clonal pancreatic beta-cells. 140 Mar

The monohydroxy bile acid taurolithocholate (TLC) causes a rapid and transient increase in free cytosolic Ca2+ concentration ([Ca2+]i) in suspensions of rat hepatocytes similar to that elicited by the InsP3-dependent hormone vasopressin. The effect of the bile acid is due to a mobilization of Ca2+, independent of InsP3, from the endoplasmic reticulum (ER). Short-term preincubation of cells with the phorbol ester 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA), which activates protein kinase C (PKC), blocked the increase in [Ca2+]i induced by TLC, but did not alter that mediated by vasopressin. We obtained the following results, indicating that the effect of PMA is mediated by the activation of PKC. (1) Phorbol esters were effective over a concentration range where they activate PKC (IC50 = 0.5 nM); (2) phorbol esters that do not activate PKC did not inhibit the effects of TLC; (3) the permeant analogue oleoylacetylglycerol mimicked the inhibitory effect of PMA; (4) lastly, the inhibition of the TLC-induced Ca2+ mobilization by phorbol esters was partially prevented by preincubating the cells with the PKC inhibitors H7 and AMG-C16. Preincubating hepatocytes with PMA had no effect on the cell uptake of labelled TLC, indicating that the phorbol ester does not interfere with the transport system responsible for the accumulation of bile acids. In saponin-treated liver cells, PMA added before or after permeabilization failed to abolish TLC-induced Ca2+ release from the ER. The possibility is discussed that PMA, via PKC activation, may alter the intracellular binding or the transfer of bile acids in the liver.
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PMID:Taurolithocholate-induced Ca2+ release is inhibited by phorbol esters in isolated hepatocytes. 144 48

Incubation of Swiss 3T3 cells with [2-3H]adenine, as in other cell types, reveals the ADP-ribosylation of GRP78 (the 78-kDa glucose-regulated protein, also known as BiP, the immunoglobulin heavy chain-binding protein), a resident endoplasmic reticulum protein that assists in the processing of proteins destined for secretion or cell surface expression. Here we show that Pasteurella multocida toxin, a potent growth factor for cultured fibroblasts, decreased the ADP-ribosylation of GRP78/BiP to 16 +/- 6% of the control value (n = 23). The action of the toxin occurred after a lag period, was blocked by lysosomotrophic agents, and potentiated by increased incubation time (ED50 4 ng/ml and 1 ng/ml in 4 and 8 h, respectively), thus indicating that the toxin enters the cells to act. Bombesin and platelet-derived growth factor (PDGF) similarly decreased the ADP-ribosylation of GRP78/BiP (ED50 0.5 nM and 2.5 ng/ml, respectively) but acted more rapidly than the toxin. Signaling pathways activated by the toxin, bombesin, and PDGF had effects on the ADP-ribosylation of GRP78/BiP. Thus, activation of protein kinase C alone by phorbol 12,13-dibutyrate was partially effective, and down-regulation of protein kinase C attenuated but did not block the action of the toxin, bombesin, and PDGF. Agents that mobilize Ca2+ from the endoplasmic reticulum (A23187, ionomycin, and thapsigargin) caused a decrease in the ADP-ribosylation of GRP78/BiP that was similar in magnitude to that achieved by the toxin, bombesin, and PDGF, implicating a role for inositol 1,4,5-trisphosphate-mediated Ca2+ mobilization in the action of the mitogenic agents. The growth factor-induced decrease in the ADP-ribosylation of GRP78/BiP may represent its conversion from an inactive to an active state.
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PMID:Interconversion of GRP78/BiP. A novel event in the action of Pasteurella multocida toxin, bombesin, and platelet-derived growth factor. 146 24

A transactivating function generated by carboxy-terminal truncation of the HBV envelope proteins has been recently described. To characterize the preS/S protein domains responsible for transactivation, preS1/S2/S and preS2/S 3' deletion mutants under the control of the adenoviral major late promoter were tested for their transactivating potential in cotransfection experiments using the c-myc and c-fos regulatory sequences as targets. Deletion of the carboxyterminal hydrophobic domain of the S protein and the presence of the endoplasmic reticulum insertion signal I (ER signal I) are required for the generation of the preS/S transactivating function. Multiple transcription factors binding sites (i.e., TRE, SRE, and NFkB sites) mediated the truncated preS/S-induced activation of the target regulatory sequences. The transactivation phenomenon is linked, at least in part, to the protein kinase C signaling pathway.
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PMID:Characterization of the hepatitis B virus preS/S region encoded transcriptional transactivator. 154 61

To evaluate possible involvement of phospholipid metabolism and related second messenger systems in the selective neuronal damage after ischemia, we measured changes of polyphosphoinositides (PPIs) and free fatty acids (FFAs) in a model of 5-min or 10-min ischemia and reperfusion in gerbils. The binding activity of 3H-phorbol 12,13-dibutyrate (PDBu) for protein kinase C (PKC) and 3H-inositol 1,4,5-triphosphate (IP3) for IP3 receptors was demonstrated autoradiographically. Induction of 70 KDa heat shock protein (HSP70) mRNA and amyloid precursor protein (APP) mRNA was also examined using Northern blot analysis. In the parietal cortex (an area resistant to transient ischemia), PPIs decreased during ischemia and recovered rapidly after reperfusion. However, recovery did not occur in the hippocampal CA1 area (an area more vulnerable to transient ischemia). In the cortex, arachidonic acid (AA) increased during ischemia and returned to baseline by 7 days after reperfusion; in the CA1 area, the AA level remained elevated even after 7 days of reperfusion. PDBu binding decreased in CA1 cells after 2 days of reperfusion. IP3 binding began to decrease at 5 hr of reperfusion, which is far earlier than either the onset of decreased PDBu binding or the observation of neuronal damage by light microscopy. The induction of HSP70 mRNA occurred, but the induction of APP mRNA did not. Regional differences in the induction of HSP70 mRNA were found; CA1 cells produced less HSP70 mRNA than cortical cells 8 hr after transient ischemia. These results suggest that CA1 cell membranes may not recover after transient ischemic attack, and that the membranes of the endoplasmic reticulum, which have IP3 receptors, may undergo alterations earlier than cytoplasmic membranes. The variable induction of HSP70 mRNA may be related to regional differences in vulnerability in cortical and hippocampal CA1 cells after transient ischemia. Involvement of excitatory neurotransmission in the induction of HSP70 has been suggested. The combined data may support a role for inositol phospholipid metabolism, changes in related second messenger systems, and induction of HSP70 in the excitotoxic mechanism of hippocampal CA1 neuronal damage, death, and repair.
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PMID:Phospholipid metabolism and second messenger system after brain ischemia. 163 89

C-terminal truncation of the middle surface antigen from hepatitis B virus (MHBs) gives rise to a novel transactivating protein, called MHBst. In this study we show that MHBst like the HBx protein of HBV, can cause nuclear appearance of NF-kappa B DNA binding activity and induce various kappa B-controlled reporter genes. While an inhibitor of protein kinase C could not block gene induction by MHBst, the antioxidants N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) could potently suppress transactivation at mM and microM concentrations, respectively. Also, kappa B-dependent gene induction by the transactivator HBx was blocked. The effects were selective because PDTC did not interfere with MHBst and HBx-induced activation of the c-fos promoter/enhancer, nor with the basal activity of several other reporter genes lacking functional NF-kappa B binding motifs. Our data suggest that induction of a prooxidant state is crucial for the activation of NF-kappa B by MHBst and HBx and might be related to the hepatocarcinogenic potential of the viral proteins. MHBst had a subcellular localization unusual for a viral transactivator: it appeared to be an integral membrane protein of the endoplasmic reticulum.
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PMID:Hepatitis B virus transactivator MHBst: activation of NF-kappa B, selective inhibition by antioxidants and integral membrane localization. 163 69

Experiments were designed to characterize the hormone sensitive transport of Ca2+ from the external media into rat hepatocytes maintained in culture. In the absence of added vasopressin, hepatocytes were nearly impermeable to Ca2+, whereas a significant and rapid influx of Ca2+ could be detected when external Ca2+ was added to hepatocytes after the addition of 20 nM vasopressin. The transport was measured as the initial rate of increase of free intracellular Ca2+ [( Ca2+]i) after Ca2+ addition to the external media. Most data were obtained from the majority of cells on a coverslip immersed in a spectrophotometric cuvette, but selected data were obtained by measuring Ca2+ changes in single cells. Ca2+ influx measured using a large number of cells was similar to data obtained using single cells. The Vmax of Ca2+ influx was 140 nM/s. Ca2+ transport was competitive with H+ so that the Km was 17.4 mM at pH 6.8, 3.7 mM at pH 7.4 and 1.8 mM at pH 7.8. Ca2+ influx was insensitive to external K+ (1 to 70 mM) and to the presence of 5 nM valinomycin, suggesting that it was independent of the electrical potential gradient across the plasma membrane. Transport also appeared to be insensitive to the activity of protein kinase C, which was varied by addition of the activator, 12-myristate 13-acetate phorbol ester, and by addition of the kinase inhibitor, staurosporine. Stimulation of transport following vasopressin addition exhibited a delay with a t1/2 of approximately 30 s. A vasopressin antagonist blocked the activation of transport, if added prior to vasopressin. However, experiments designed to determine the effect of hormone occupancy per se on transport activity indicated that continued hormone occupancy was not required. When the external medium was nominally Ca2+ free and an antagonist was added 1 min after vasopressin, Ca2+ entry, even 8 min after antagonist addition, was rapid. Conversely, preincubation with vasopressin antagonist in medium containing 0.5 mM Ca2+ dramatically lowered plasma membrane Ca2+ permeability. The ER Ca2+ pool emptied by vasopressin was refilled in the presence of vasopressin antagonist plus 0.5 mM Ca2+, but did not refill when the medium contained no added Ca2+. Under the conditions of these experiments, the Ca2+ levels of the ER hormone-sensitive Ca2+ pool were estimated as well as intracellular concentrations of inositol-1,4,5-trisphosphate. The Ca2+ levels of the endoplasmic reticulum correlated inversely with plasma membrane Ca2+ permeability, whereas cellular concentrations of inositol-1,4,5-trisphosphate did not correlate with Ca2+ permeability.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of plasma membrane permeability to calcium in primary cultures of rat hepatocytes. 165 96


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