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)

The phenethyl ester analogues of cholecystokinin, OPE and JMV-180, are fully efficacious rat pancreatic secretagogues which, unlike cholecystokinin (CCK), do not elicit supramaximal inhibition of secretion, and stimulate a sustained rise of cytosolic calcium ([Ca2+]i) above basal levels. We have recently shown that low-level protein kinase C (PKC) activation by preincubation of acini with 1 nM 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or minimally secreting concentrations of PKC-activating receptor agonists (1 pM CCK-8, 0.1 microM carbachol or 10 pM bombesin) cause supramaximal inhibition of OPE-stimulated enzyme secretion. We now show that treatment of acini under these conditions also suppresses the sustained rise of [Ca2+]i stimulated by OPE to basal levels in these cells, without changing the initial OPE-stimulated [Ca2+]i peak. The resultant pattern of calcium signalling is similar to that evoked by supramaximal concentrations of native CCK. This suggests that even low concentrations of PKC-activating agonists have the potential to induce inhibitory effects on Ca2+ mobilization and that this kinase is important in generating the supramaximal inhibition observed in response to CCK.
Pancreas 1994 Jul
PMID:Low concentrations of protein kinase C-activating agonists suppress cholecystokinin-OPE-evoked Ca2+ mobilization in rat pancreatic acini. 793 93

In this investigation we studied pancreastatin (PST) secretion from a human PST producing cell line (QGP-1N) in response to various secretagogues. Immunocytochemical study revealed the immunoreactivity of PST and somatostatin (SMT) in the same cells of a monolayer culture. Ki-ras DNA point mutation on codon 12 was found. Carbachol stimulated secretion of PST and SMT and intracellular Ca2+ mobilization in the range of 10(-6)-10(-4) M. The secretion and Ca2+ mobilization were inhibited by atropine, a muscarinic receptor antagonist. Phorbol ester and calcium ionophore (A23187) stimulated secretion of PST and SMT. The removal of extracellular calcium suppressed both secretions throughout stimulation with 10(-5) M carbachol. Fluoride, a well-known activator of guanine nucleotide binding (G) protein, stimulated intracellular Ca2+ mobilization and secretion of PST and SMT in a dose-dependent manner in the range of 5-40 mM. Also, 10(-5) M carbachol and 20 mM fluoride stimulated inositol 1,4,5-triphosphate production. However, cholecystokinin and gastrin-releasing peptide did not stimulate Ca2+ mobilization or secretion of the two peptides. These results suggest that secretion of PST and SMT from QGP-1N cells is regulated mainly by acetylcholine in a parallel fashion through muscarinic receptors coupled to the activation of polyphosphoinositide breakdown by a G-protein and that increases in intracellular Ca2+ and protein kinase C play an important role in stimulus-secretion coupling.
Pancreas 1993 May
PMID:Parallel secretion of pancreastatin and somatostatin from human pancreastatin producing cell line (QGP-1N). 809 76

The mechanisms underlying the insulinotropic action of gastrin releasing peptide (GRP) were examined in normal mouse islets. GRP (100 nM) enhanced insulin secretion at glucose concentrations of > or = 11.1 mM (p < 0.05) but only in the presence of extracellular Ca2+. The insulinotropic effect of the peptide studied during perifusion at 16.7 mM glucose was transient and vanished in time. GRP stimulated, transiently, 45Ca2+ efflux from 45Ca(2+)-prelabeled islets, both in the presence and in the absence of extracellular Ca2+ (p < 0.05), suggesting that GRP releases Ca2+ from intracellular stores. Similarly, GRP increased 86Rb+ efflux from 86Rb(+)-prelabeled islets both in the presence and in the absence of extracellular Ca2+ (p < 0.001). In contrast to GRP-induced insulin secretion, the GRP-induced 86Rb+ efflux was sustained throughout the stimulation period, suggesting that increased K+ conductance may be involved in the vanishing effect of GRP on insulin secretion. Furthermore, both inhibition of protein kinase C (PKC) by staurosporine (1-10 microM) and down-regulation of PKC activity by long-term incubation with the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate inhibited GRP-stimulated insulin secretion (p < 0.05). These results indicate that GRP activates PKC by an action involving liberation of Ca2+ from Ca2+ stores. Therefore, also the influence of GRP on phosphoinositide hydrolysis was studied by means of 3H efflux from myo-[2-3H]inositol prelabeled islets. However, GRP did not stimulate the 3H efflux. In contrast, GRP-stimulated insulin secretion was abolished by an inhibitor of phospholipase D, wortmannin (1 microM). The results suggest that GRP transiently potentiates glucose-induced insulin secretion by an action mediated by PKC activated by diacylglycerol formed through activation of phospholipase D. Simultaneously, an as yet unknown mechanism liberating Ca2+ from intracellular stores is activated.
Pancreas 1996 Jan
PMID:Studies on the mechanisms by which gastrin releasing peptide potentiates glucose-induced insulin secretion from mouse islets. 892 19

In this article, the "tethered ligand" thrombin receptor was identified on human pancreatic tumor cells, MIA PaCa-2, using immunofluorescence studies with a monoclonal anti-thrombin receptor antibody. Pharmacological characterization, using 3H-labeled thrombin receptor activating peptide-6 (TRAP-6) as radioligand, demonstrated a single class of high-affinity binding sites (KD = 9.1+/-1.8 x 10(-7) M) and a binding capacity of 13.9+/-0.7 fmol/mg protein. These binding sites represent functional thrombin receptors, as shown by alpha-thrombin- and TRAP-6-induced mobilization of free intracellular calcium, protein kinase C translocation from cytosol to the cell membrane, and stimulation of DNA synthesis in MIA PaCa-2 cells. These results provide the first identification of tethered ligand thrombin receptor in human pancreatic cancer cells and suggest thrombin receptor involvement in mechanisms of human pancreatic tumor progression.
Pancreas 1998 Mar
PMID:Characterization of functional thrombin receptors in human pancreatic tumor cells (MIA PACA-2). 951 Jan 43

Although hyperlipidemia is frequently associated with hyperinsulinemia. the stimulation of insulin secretion by fatty acids in the in vitro studies has remained a matter of constant debate, partly because of the uncertainty about a clearly defined mechanism to explain such a direct effect. In this study, we used a pharmacologic approach to test the hypothesis that protein kinase C (PKC) signal-transduction pathway is involved in fatty acid-stimulated insulin secretion. Isolated rat islets were perifused with either palmitate (C(16:0)) or linoleate (C(18:2)) in the absence or presence of selective inhibitors of PKC isoenzymes. Our results suggest a role for Ca2+-independent PKC isoenzymes in the signal transduction of fatty acid-stimulated insulin secretion. The data imply that either the nonconventional and/or atypical isoforms of PKC are involved in the stimulation of insulin release induced by fatty acids.
Pancreas 2000 Apr
PMID:Role of protein kinase C isoenzymes in fatty acid stimulation of insulin secretion. 1076 51

The mouse intestinal neuroendocrine tumor cell line STC-1 secretes cholecystokinin (CCK) and other hormones. We investigated the role of Ca2+, calmodulin (CaM), and protein kinase C (PKC) in the regulation of CCK release from STC-1 cells. Phorbol 12-myristate 13-acetate (TPA) significantly stimulated CCK release. Staurosporine significantly inhibited CCK release from STC-1 cells stimulated by TPA in a dose-dependent manner. The absence of extracellular calcium completely inhibited CCK release from TPA-stimulated STC-1 cells. Neurotensin did not stimulate CCK release from these cells. W-7, a CaM antagonist, reduced CCK release from STC-1 cells stimulated by bombesin in a dose-dependent manner. These findings suggest that CaM and PKC play an important role in the regulation of CCK release from STC-1 cells stimulated by bombesin.
Pancreas 2000 Oct
PMID:Involvement of calmodulin and protein kinase C in cholecystokinin release by bombesin from STC-1 cells. 1103 66

It has been recently reported that kinases that belong to the mitogen-activated protein kinase (MAPK) family are rapidly activated by cholecystokinin (CCK) in rat pancreas both in vitro and in vivo. It is known that reactive oxygen species (ROS) play an important role in the pathogenesis of acute pancreatitis induced by supraphysiologic stimulation with CCK analogue, cerulein. The aim of our study was to evaluate whether MAPKs are activated by ROS in pancreatic acini. The activity of MAPK, c-Jun amino-terminal kinase (JNK), and p38 MAPK was determined in isolated rat pancreatic acinar cells by means of Western blotting, with the use of specific antibody that recognizes active, dually phosphorylated kinases. Incubation of acini with ROS donors, hydrogen peroxide (H2O2) and/or menadione (MND), strongly activated all three kinases. Activation of these kinases by ROS, but not by CCK, was substantially inhibited by pretreatment of acini with antioxidant N-acetylo-L-cysteine (NAC). Whereas CCK-induced activation of MAPK or JNK was totally or partially blocked by protein kinase C (PKC) inhibitor GF-109203X, ROS-induced activation of MAPK, JNK, and p38 MAPK was PKC independent. In conclusion, ROS strongly activate MAPK, JNK, and p38 MAPK in pancreatic acinar cells. It may be of importance in acute pancreatitis, because ROS are involved in the pathogenesis of this disease.
Pancreas 2000 Nov
PMID:Reactive oxygen species activate mitogen-activated protein kinases in pancreatic acinar cells. 1107 92

In several models of insulin resistance, cholinergically induced insulin secretion is augmented. We studied here whether this also is present in the spontaneously diabetic GK (Goto-Kakizaki) rat pancreas. Using carbachol (50 micromol/L), enhanced insulin release was elicited in perfused pancreas under normal or depolarized conditions in GK compared with control rats at 3.3 mmol/L glucose (p < 0.03). Carbachol fully normalized insulin secretion in GK rats at 16.7 mmol/L glucose through an effect abolished by atropine. Similarly, direct stimulation of protein kinase C (PKC) with the DAG-permeable compound 1-oleoyl-2-acetyl-sn-glycerol (OAG, 300 micromol/L) induced more pronounced insulin release in GK islets than in control islets. The diacylglycerol (DAG) lipase inhibitor RHC-80267 (35 micromol/L) significantly reduced carbachol effects in control and GK islets, but had no effect on OAG-induced insulin release. The enhanced insulinotropic effects of carbachol in GK islets was not accompanied by increased cyclic adenosine monophosphate (cAMP) or arachidonic acid (AA) formation in GK when compared with control islets. In conclusion, cholinergic stimulation induced enhanced insulin release in diabetic GK islets. This is largely mediated through mechanisms involving hydrolysis of DAG to AA and interaction with exocytotic steps of insulin release.
Pancreas 2001 Mar
PMID:Carbachol restores insulin release in diabetic GK rat islets by mechanisms largely involving hydrolysis of diacylglycerol and direct interaction with the exocytotic machinery. 1124 71

The ultratrace elements vanadate, tungstate, and molybdate exhibit significant antihyperglycemic effects in both type 1 and 2 diabetic animals, but possible effects on the function of pancreatic beta cells are understudied. In the present study, clonal BRIN BD11 cells were cultured for 3 days with each ultratrace element to establish doses lacking detrimental effects on viable beta cell mass. Vanadate treatment (4 micromol/L) had no effect on cellular insulin content but improved glucose-induced insulin secretory responsiveness. However, insulin secretion mediated by PKA and PKC activation was desensitized in vanadate-treated cells. Culture with tungstate (300 micromol/L) and molybdate (1 mmol/L) increased cellular insulin content and enhanced basal insulin release and the responsiveness to glucose and a wide range of other secretagogues. These observations suggest significant effects of ultratrace elements on pancreatic beta cells that may contribute to their antihyperglycemic action.
Pancreas 2004 May
PMID:Long-term beneficial effects of vanadate, tungstate, and molybdate on insulin secretion and function of cultured beta cells. 1509 51

Brain-Pancreas Relative Protein (BPRP) is a novel protein found in our laboratory. In previous study we observed a significant reduction in BPRP in ischemic brain of rat. Here we undertook this study to explore the possible mediating mechanism by which oxygen and glucose-deprivation culture (OGD), a model of ischemia in vitro, decreased the expression of BPRP in PC12 cells. BPRP was found to be expressed in PC12 cells and OGD caused a significant reduction in BPRP expression. The effect of OGD was primarily mediated by reactive oxygen species (ROS) because OGD upregulated the production of ROS and the inhibitors of protein kinase C, calmodulin, free radical scavengers reduced OGD-induced ROS production, while increased the expression of BPRP in PC12 cells. These data indicate that OGD decreases the expression of BPRP via enhanced formation of intracellular ROS.
 ...
PMID:Reduction in the in vitro expression of Brain-Pancreas Relative Protein by oxygen and glucose-deprivation. 1695 35


<< Previous 1 2 3 Next >>