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)

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.
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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

In striatal astrocytes, receptors for the vasoactive peptide endothelin (ET) are associated with several intracellular signalling pathways: ET-1 increases the breakdown of phosphoinositides, induces a sustained influx of Ca2+ and inhibits the isoproterenol-induced formation of cAMP (Marin et al., J. Neurochem., 56, 1270 - 1275, 1991). In the present study, it will be shown that ET-1 and ET-3 markedly stimulate the release of arachidonic acid (AA) from cultured astrocytes from the mouse striatum (EC50=3 and 7 nM for ET-1 and ET-3, respectively), mesencephalon and cerebral cortex. The ET-1-evoked release of AA probably resulted from the activation of a phospholipase A2, since it required extracellular Ca2+ and was prevented by mepacrine but not by RHC 80267, an inhibitor of diacylglycerol lipase. The ET-1-induced release of AA was shown to be partially mediated by a guanine nucleotide-binding protein sensitive to pertussis toxin but not to cholera toxin. A cAMP-dependent process is not involved since the ET-1-evoked release of AA was not affected when cells were incubated with either isoproterenol or 8-bromo-cAMP. The ET-1-evoked release of AA could be mimicked by the co-application of a calcium ionophore and a protein kinase C activator. However, staurosporine, a potent inhibitor of protein kinase C, which blocked the release of AA induced by the combined application of ionomycin and phorbol 12-myristate 12-acetate (PMA), was without effect on the ET-1-evoked response, indicating that protein kinase C is not directly involved in the ET-1-induced release of AA. Furthermore, the responses induced by ET-1 and by PMA were found to be additive. These results suggest that (1) ET-1 receptors are coupled to the release of AA by a mechanism independent of both protein kinase C activation and the adenylate cyclase pathway, possibly via the activation of phospholipase A2, (2) different mechanisms (or different phospholipase A2 subtypes) are involved in the control of AA release in astrocytes.
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PMID:Endothelin-evoked Release of Arachidonic Acid from Mouse Astrocytes in Primary Culture. 1210 34

Guinea pig gallbladder muscle strips were used to investigate the contribution of different sources of diacylglicerol (DAG) in the cholecystokinin (CCK)-induced contraction. The involvement of arachidonic acid (AA) in this response was also investigated. Three distinct pathways for DAG production were investigated with specific phospholipase (PL) inhibitors. U-73122 (10 microM) was used for inhibition of phosphoinositide-specific-PLC (PI-PLC), D-609 (100 microM) for phosphatidylcholine specific-PLC (PC-PLC), and propranolol (100 microM) for phospholipase D (PLD). Separate or combined inhibition of each of these enzymes showed that the CCK-induced output of DAG involves the parallel activation of each of these phospholipases. Thus, after inhibition of a PL subtype, the remaining subtypes were able to functionally compensate in mediating CCK-induced contraction. Inhibition of AA production via DAG-lipase or phospholipase A(2) (PLA(2)) was accomplished using RHC-80267 (40 microM), mepacrine (100 microM) and 4-BPB (100 microM). These inhibitors diminished contractile response, indicating that AA is an important modulator of CCK-induced contraction. Indomethacin (10 microM) and nordihydroguaiaretic acid (NDGA, 100 microM), which inhibit subsequent steps in AA metabolism through the cyclooxygenase and 5-lipooxygenase pathways, also inhibited contractions. Taken together, these results show that CCK redundantly activates PC-PLC, PI-PLC and PLD, to produce DAG, which in turn stimulates PKC and provides a substrate for the generation of AA. sPLA(2) is also a source of AA, whose metabolites are, in part, responsible for determining the magnitude of the CCK-evoked contraction.
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PMID:Contribution of different phospholipases and arachidonic acid metabolites in the response of gallbladder smooth muscle to cholecystokinin. 1223 20

In small segments of circular smooth muscle isolated from the guinea-pig gastric antrum, the effects of RHC-80267, an inhibitor of diacylglycerol lipase, were investigated both on regenerative slow potentials (either occurring spontaneously or as the result of a depolarizing intracellular current injection) and on the actions of acetylcholine (ACh). As diacylglycerol is a known activator of protein kinase C (PKC), it would therefore be expected that RHC-80267 would activate PKC indirectly. In circular smooth muscle bundles, spontaneously generating slow potentials recorded simultaneously from two given cells were synchronized, indicating that these two cells were electrically coupled. RHC-80267 (0.3-1 microM) increased the frequency of slow potential generation, with no alteration to the amplitude of either the slow potentials or the resting membrane potential. Synchronous electrical activity in a given pair of cells was also unchanged by RHC-80267, indicating that intercellular electrical coupling was not altered. The input resistance of smooth muscle cells calculated from the amplitude of electrotonic potentials produced by injection of current was not significantly altered by RHC-80267. The refractory period for the generation of slow potentials evoked by depolarizing stimuli was about 8 s, and it was decreased to about 5 s by RHC-80267, with no significant alteration to the amplitude of spontaneous or evoked slow potentials. ACh (0.5 microM) depolarized the membrane by about 5 mV and increased the amplitude and frequency of slow potentials. The actions of ACh on the frequency of slow potentials were enhanced by RHC-80267, with no alteration to the amplitudes of both the ACh-induced depolarization and slow potentials. These results support the idea that PKC is involved in determining the frequency of slow potentials, by shortening the refractory period for excitation of gastric smooth muscle cells.
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PMID:Effects of RHC-80267, an inhibitor of diacylglycerol lipase, on excitation of circular smooth muscle of the guinea-pig gastric antrum. 1271 22

The hypertrehalosemic hormones, HTH-I and HTH-II, activate trehalose synthesis and increase the rate of sugar efflux from Periplaneta americana fat body in vitro. These processes are unaffected by the diacylglycerol, 1-oleyl-2-acetyl-sn-glycerol, an activator of protein kinase C. Similarly, H-7 and spingosine, inhibitors of protein kinase C, are also inactive against trehalose efflux. The possibility that diacylglycerol lipase might generate an active fatty acid species was ruled out because of the failure of the inhibitor RHC-80267 to inhibit trehalose efflux. Activation of trehalose efflux from the intact fat body by HTH-I was strongly inhibited in a concentration dependent manner by the cyclooxygenase inhibitors indomethacin and diclofenac, but not by acetylsalicylic acid. Nordihydroguaiaretic acid, a lipoxygenase inhibitor, also blocked HTH-I activated trehalose efflux in a concentration dependent fashion. The phospholipase A(2) inhibitors mepacrine and 4'-bromophenacyl bromide were also effective in decreasing the efflux of trehalose from HTH-I challenged fat body. The data suggest possible roles for arachidonic acid metabolites in the regulation of trehalose synthesis and in the efflux of the sugar from the fat body.
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PMID:Evidence for the participation of arachidonic acid metabolites in trehalose efflux from the hormone activated fat body of the cockroach (Periplaneta americana). 1277 Apr 11

1 Endothelial cells play an important role in the modulation of vascular tone because of their ability to produce vasoactive substances such as prostacyclin (PGI(2)). Cell-cell contact between human umbilical vein endothelial cells (HUVEC) and peripheral blood lymphocytes has been shown to stimulate endothelial PGI(2) synthesis by increasing free arachidonic acid availability through endothelial cytosolic phospholipase A2 (cPLA(2)) activation. In this study, we sought to determine whether phospholipase C (PLC) and D (PLD) activation also contributes, besides cPLA(2), to the lymphocyte-induced PGI(2) synthesis in HUVEC, and to delineate further the potential mechanisms of cPLA(2) activation triggered by the interaction of HUVEC with lymphocytes. 2 Pretreatment of endothelial cells with the PI-PLC inhibitor U-73122 before the coincubation with lymphocytes markedly inhibited the PGI(2) output whereas the diacylglycerol (DAG) lipase inhibitor RHC 80267 and ethanol had no effect. These results suggest that PLC may be involved through inositol trisphosphate generation and calcium mobilization, and that neither DAG nor phosphatidic acid (PtdOH) was used as sources of arachidonic acid. 3 The stimulated PGI(2) synthesis was protein kinase C (PKC)-independent but strongly inhibited by the mitogen-activated protein kinase kinase (MEK) inhibitors PD98059 and U-0126 and by the Src kinase inhibitor PP1. 4 Immunoblot experiments showed an increased phosphorylation of the extracellular signal-regulated kinases 1/2 (ERK1/2) upon lymphocyte addition till 4 h coincubation. Phosphorylation was markedly inhibited by U-0126 and PP1 addition. 5 Collectively, these results suggest that the signaling cascade triggered by lymphocytes in endothelial cells involves an Src kinase/ERK1/2 pathway leading to endothelial cPLA(2) activation.
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PMID:Mechanisms involved in the stimulation of prostacyclin synthesis by human lymphocytes in human umbilical vein endothelial cells. 1277 Sep 37

The intracellular signalling pathway for alpha-adrenoceptor-mediated negative inotropy was studied pharmacologically in isolated adult mouse ventricle. The negative inotropy was inhibited by GF-109203X, a nonselective protein kinase C inhibitor. Phorbol 12-myristate 13-acetate also produced sustained negative inotropy, which was inhibited by KB-R7943, a Na(+)/Ca(2+) exchanger inhibitor. The alpha-adrenoceptor-mediated negative inotropy was augmented by RHC-80267, a diacylglycerol lipase inhibitor, but was inhibited either by C(2)-ceramide, a phospholipase D inhibitor, and high concentration of propranolol (50 micro M), which inhibits phosphatidate phosphohydrolase. The inotropy was not affected by U-73122, a phospholipase C inhibitor. Lavendustin-A, a tyrosine kinase inhibitor, also inhibited the negative inotropy. These findings suggest that alpha-adrenoceptor-mediated negative inotropy in adult mouse ventricle is mediated by activation of tyrosine kinase, the phospholipase D-phosphatidate phosphohydrolase pathway, and protein kinase C.
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PMID:Pharmacological evidence for involvement of phospholipase D, protein kinase C, and sodium-calcium exchanger in alpha-adrenoceptor-mediated negative inotropy in adult mouse ventricle. 1289 Aug 84

Stimulation of G-protein coupled membrane receptors linked to phospholipase C results in production of the second messengers diacylglycerol and inositol-1,4,5-trisphosphate (IP3). IP3 releases Ca2+ from the endoplasmic reticulum, which triggers increased Ca2+ influx across the plasma membrane, so-called capacitative calcium entry. DAG can also activate plasma membrane calcium-permeable channels but the mechanism is still not fully understood. In the pregnant human myometrial cell line PHM1 and in primary myometrial cells, 1-oleoyl-2-acetyl-sn-glycerol (OAG), a membrane-permeant analogue of diacylglycerol, induced variable oscillatory patterns of intracellular free Ca2+. Similar behavior was seen with Sr2+ entry. The Ca2+ oscillations were not blocked by a broad spectrum of protein kinase C inhibitors, including chelerytrine, bisindolylmaleimide I and calphostin C, and were enhanced and prolonged by RHC-80267, an inhibitor of diacylglycerol lipase. The OAG-induced oscillatory response was not dependent on Ca2+ release from the endoplasmic reticulum but required extracellular Ca2+. Our results indicate that diacylglycerol directly activates cation channels in PHM1 and primary myometrial cells and promotes intracellular Ca2+ oscillations by actions independent of intracellular Ca2+ -ATPase activity and protein kinase C involvement.
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PMID:Stimulation of intracellular Ca2+ oscillations by diacylglycerol in human myometrial cells. 1519 63

The diacylglycerol lipase inhibitor 1,6-bis(cyclohexyloximinocarbonylamino) hexane (RHC-80267) was tested for its effect on acetylcholine-evoked relaxation in rat mesenteric artery. In artery contracted with either noradrenaline or KCl, RHC-80267 (0.1-10 muM) potentiated the relaxation evoked by acetylcholine. The effect of RHC-80267 was not affected by nitric oxide synthase inhibition or by inhibitors of protein kinase C or of phospholipase A(2). The diacylglycerol analogue 1-oleoyl-2-acetyl-sn-glycerol did not change the relaxation to acetylcholine. RHC-80267 did not affect the relaxation evoked by carbachol, by the nitric oxide donor SNAP (S-nitroso-N-acetylpenicillamine) or by the K(+) channel opener cromakalim. Neostigmine, a cholinesterase inhibitor, produced the same effect as RHC-80267 on acetylcholine-evoked relaxation. When tested on cholinesterase in brain homogenate, RHC-80267 concentration-dependently inhibited cholinesterase activity with an IC(50) of 4 muM. These results indicate that the potentiation of acetylcholine-evoked responses by RHC-80267 in rat mesenteric artery is caused by the inhibition of the cholinesterase activity in the vascular wall.
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PMID:The diacylglycerol lipase inhibitor RHC-80267 potentiates the relaxation to acetylcholine in rat mesenteric artery by anti-cholinesterase action. 1595 63

The involvement of Ca(2+) sensitization mediated through Rho kinase in the contractility of rat epididymal vas deferens was investigated using Rho kinase inhibitors, trans-4-[(1R)-1-aminoethyl]-N-4-pyridinilcyclohexanecarboxamide dihydrochloride (Y-27632) and 1-(5-isoquinolinesulphonyl)homopiperazine (HA 1077), in comparison with myosin light chain kinase (MLCK) inhibitors, wortmannin and 1-(5-chloronaphthalenesulphonyl)homopiperazine (ML-9) and agents that affect protein kinase C (PKC) and non-receptor tyrosine kinase intracellular signalling. 2 In Ca(2+)-free/ethyleneglycol-bis-(beta-aminoethylether)N,N,N('),N(')-tetraacetic acid (EGTA) (1 mM) medium, noradrenaline evoked sustained contractions. Y-27632 and HA 1077 caused a concentration-dependent inhibition and complete relaxation (IC(50), 1.08 and 1.75 microM respectively). The Ca(2+)-free contraction was reduced by wortmannin (10 microM) or ML-9 (10 microM) but not by inhibitors of diacylglycerol metabolism, 3-[2-[4[bis(4-Fluoropheny)methylene]-1-piperidinyl]-2,3-dihydro-2-thioxi-4(H)-quinazolinone (R59949) (10 microm) or 1,6-bis(cyclohexyloximinocarbonylamino)hexane (RHC-80267) (10 microM) or by the phospholipase A(2) (PLA(2)) inhibitor, quinacrine (up to 100 microM) or tyrosine kinase inhibitor, genistein (30 microM). 3 In the presence of Ca(2+) (2.5 mM), noradrenaline (100 microM) evoked rhythmic activity and biphasic tonic contractions. Y-27632 (1-10 microM) or HA 1077 (1-10 microM) reduced the amplitude of rhythmic activity and tonic contractions. ML-9 (10 microM) attenuated the occurrence of rhythmic activity and modestly reduced the tonic contractions. ML-9 (10 microM) combined with Y-27632 (10 microM) significantly reduced the tonic contractions. ML-9 (30 microM) alone (or combined with Y-27632 10 microM) suppressed the rhythmic activity and substantially reduced (or abolished) the tonic contractions. 4 Contractions evoked by high [K(+)](o) (120 mM) or alpha,beta-methylene ATP (10 microM) were reduced significantly by Y-27632 (1-3 microM) indicating that the Rho kinase signalling pathway is activated by direct tissue depolarization or by stimulation of ligand-gated P(2X) purinoceptors. 5 Collectively, these results indicate that Ca(2+)-sensitization mediated by Rho kinase is involved in agonist- or depolarization-induced contraction of rat epididymal vas deferens. It is the major contractile mechanism underlying noradrenaline-induced Ca(2+)-free responses. It contributes to Ca(2+)-dependent rhythmic contractility and optimizes the development of full contractile tension triggered through calmodulin/MLCK activation by stimulated influx of Ca(2+).
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PMID:Attenuation of contractility in rat epididymal vas deferens by Rho kinase inhibitors. 1655 45


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