Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When ram spermatozoa were treated with Ca2+ and the ionophore A23187 to induce acrosomal exocytosis, a rise in diacylglycerol (DAG) mass was observed, concomitant with a rapid breakdown of [32P]P1-labelled phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 4-phosphate and a rise in [32P]Pi-labelled phosphatidate. Inclusion of the DAG lipase inhibitor RHC 80267 resulted in further but biphasic increases in DAG; there was an increasing accumulation of DAG with concentrations of RHC 80267 up to 10 microM, whereas higher concentrations produced lessening accumulation. Inclusion of RHC 80267 in the ionophore induction system also resulted in significant accelerations of the onset of exocytosis. In spermatozoa stimulated with Ca2+/A23187 and the DAG kinase inhibitor R59022, a similar increase in DAG levels together with stimulation of acrosomal exocytosis were observed. Preincubation of spermatozoa with sn-1-oleoyl-2-acetylglycerol, rac-1-oleoyl-2-acetylglycerol, sn-1,2-dioctanoylglycerol and sn-1,3-dioctanoylglycerol before treatment with Ca2+/A23187 resulted in a dose-dependent stimulation of exocytosis by all these isomers. Neomycin inhibited Ca2+/A23187-induced generation of DAG together with polyphosphoinositide breakdown, as well as acrosomal exocytosis. Inclusion of exogenous DAG, however, overcame the inhibitory effect of neomycin on exocytosis. Our results suggest that DAG has a key role in acrosomal exocytosis and that it acts as a messenger rather than as a substrate from which other active metabolites are generated. The lack of stereospecificity shown by the exogenous DAGs implies that DAG does not act by stimulating protein kinase C, but the metabolite's actual target in the sperm cell is as yet unclear.
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PMID:The role of diacylglycerol in the exocytosis of the sperm acrosome. Studies using diacylglycerol lipase and diacylglycerol kinase inhibitors and exogenous diacylglycerols. 131 Nov 74

We have recently shown that glutamate exerts a stimulatory action on somatostatin secretion in cortical neurons essentially through NMDA receptor sites. Here, we investigated whether arachidonic acid release could be modified after NMDA receptor activation in cortical neurons in primary culture. We also studied whether pharmacological manipulation of phospholipase A2 could modify somatostatin release. We found that both glutamate and NMDA (N-methyl-D-aspartate) stimulated [3H]arachidonic acid release. NMDA-evoked arachidonic acid release was inhibited by MK-801 and TCP (two NMDA receptor-type antagonists), or by mepacrine, an inhibitor of phospholipase A2. NMDA-induced somatostatin release was inhibited by MK-801, mepacrine and by another phospholipase A2 inhibitor, p-bromophenacylbromide (pBPB). However, responses to NMDA were unaffected by H7, NDGA (nordihydroguaiaretic acid), indomethacin or by RHC 80267 (inhibitors of protein kinase C, lipooxygenase, cyclooxygenase and diacylglycerol lipase, respectively). Mepacrine (greater than or equal to 100 microM) decreased NMDA-stimulated phosphatidylinositol (PI) hydrolysis and at higher concentrations (250 microM) was also able to inhibit basal release whereas pBPB had no effect in the range of concentrations tested. Neomycin (which inhibits phosphatidylinositol metabolism by binding strongly and selectively to inositol phospholipids) reduced by 30% the NMDA-stimulated somatostatin release, although chronic treatment of neurons with the phorbol ester 12-myristate, 13-acetate (PMA) had no effect on this response. Melittin, an activator of phospholipase A2, was able to stimulate both arachidonic acid release and somatostatin secretion. High-performance liquid chromatography (HPLC) analysis of tritiated metabolites released from cortical neurons under basal or NMDA-stimulated conditions revealed that [3H]arachidonic acid was the only metabolite detectable. Furthermore, external addition of arachidonic acid increased somatostatin secretion. Our results show a correlation between the two parameters studied.
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PMID:NMDA receptor activation stimulates phospholipase A2 and somatostatin release from rat cortical neurons in primary cultures. 135 46

12-O-tetradecanoylphorbol-13-acetate (TPA, 1 to 30 ng/ml) produced a dose-related inhibition of substance P (SP)-induced histamine release from rat peritoneal mast cells. TPA itself induced some histamine release over this concentration range (maximum release about 20% of total). Maximum inhibition of SP-induced release by TPA required preincubation with TPA for at least 10 min. The inhibitory action of TPA was observed in the absence as well as in the presence of extracellular calcium (0.4 mM). Inhibition of diacylglycerol kinase by R 59022 or of diacylglycerol lipase by RHC 80267 reduced SP-induced histamine release. Oleolylacetylglycerol (OAG, 50 microM) inhibited histamine release induced by SP but was less potent than TPA. It is concluded that protein kinase C activation in rat peritoneal mast cells is associated with inhibition of SP-induced histamine release.
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PMID:Effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on substance P-induced histamine release from rat peritoneal mast cells. 169 35

We have shown earlier that the 12-lipoxygenase product of arachidonic acid (AA), 12-hydroxyeicosatetraenoic acid (12-HETE), plays an important role in mediating angiotensin II (AII)-induced aldosterone secretion (J. Clin. Invest. (1987) 80, 1763). In the present study, we have evaluated whether diacylglycerol (DG) is the source of arachidonic acid giving rise to this 12-HETE. Treatment of rat adrenal glomerulosa cells with a DG lipase inhibitor, RHC 80267, which prevents conversion of DG to AA and HETEs, blocked AII-induced aldosterone and 12-HETE formation. In contrast, a DG kinase inhibitor, R59022, which prevents conversion of DG to phosphatidic acid, potentiated AII-induced aldosterone and 12-HETE formation. These two inhibitors block DG metabolism which would be expected to lead to increased DG levels and protein kinase C activity and AII-induced steroidogenesis. However, only R59022 potentiated AII action while RHC 80267 was inhibitory. This suggests that conversion of DG to AA and 12-HETE is important for AII action. Further proof for this was obtained by measuring [3H]AA-labeled DG levels. The combination of the inhibitors significantly potentiated AII-induced DG formation even though this same combination was inhibitory on AII-induced aldosterone and 12-HETE. Thus, the inhibitory effect of RHC 80267 is due to blockade of AA release and not of DG formation. These results suggest that DG plays a dual role in AII action, both as an activator of protein kinase C and as a source of AA for 12-HETE formation.
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PMID:Key role of diacylglycerol-mediated 12-lipoxygenase product formation in angiotensin II-induced aldosterone synthesis. 217 2

The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and the synthetic diacylglycerol, 1-oleoyl-2-acetylglycerol (OAG) were employed to investigate the consequences of protein kinase C activation in rat peritoneal mast cells. TPA (10 ng/ml) induced a biphasic release of histamine from mast cells. At short periods of incubation histamine release was low; about 10% at 10 min. At 15 min a second phase of release commenced, achieving a maximum at 90 min incubation by which time about 70% of cell histamine was released. Histamine release by TPA was dependent on glycolytic and oxidative metabolism, temperature-dependent and occurred in purified mast cells. In contrast, histamine release induced by OAG 50 micrograms/ml was maximal after 20 min. Studies using RHC 80267, a diacylglycerol (DAG) lipase inhibitor, indicated that metabolism of OAG by DAG lipase as well as spontaneous degradation accounts for the comparatively short-lived response to OAG.
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PMID:Phorbol esters induce a slow, non-cytotoxic release of histamine from rat peritoneal mast cells. 244 Feb 61

We earlier showed that the diacylglycerol (DG) lipase inhibitor, RHC 80267, increased the steady-state level of DG and inhibited the release of arachidonic acid (AA) in carbamylcholine (CCh)-stimulated pancreatic minilobules (J. F. Dixon and L. E. Hokin, (1984) J. Biol. Chem. 259, 14418-14425). There was no effect on phospholipid metabolism. We have now investigated the effect of RHC 80267 on CCh-stimulated formation of inositol monophosphate formation, cGMP formation, and amylase release. CCh (10 microM) increased cGMP formation by approximately 20-fold, and this response was inhibited 55-75% by RHC 80267 (75-100 microM). RHC 80267 had no effect on either nitroprusside- or calcium ionophore-stimulated cGMP formation, arguing against a direct inhibition of guanylate cyclase by RHC 80267. Arachidonic acid, the release of which is inhibited by RHC 80267, neither stimulated cGMP formation nor reversed the effect of RHC 80267 on CCh-stimulated cGMP formation. This suggests, but does not prove, that the rise in cGMP in response to CCh is not due to an increase in AA as has been suggested. Both phorbol myristate acetate (25 nM) and the DG kinase inhibitor R 59022 (10 microM) inhibited CCh-stimulated cGMP formation by 40%. RHC 80267 also inhibited CCh-stimulated inositol phosphate accumulation and amylase release by 60 and 40%, respectively. The data suggest that the inhibition of CCh-stimulated cGMP formation and other muscarinic responses by RHC 80267 is probably the result of feedback inhibition of the cholinergic receptor via activation of protein kinase C by the elevated DG.
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PMID:Inhibitors of diacylglycerol lipase and diacylglycerol kinase inhibit carbamylcholine-stimulated responses in guinea pig pancreatic minilobules. 244 62

1. RHC 80267 and R59 022 are selective inhibitors of diacylglycerol (DAG) lipase and DAG kinase enzymes respectively. These inhibitors were examined with regard to their effects on oleoylacetylglycerol (OAG)-and anti-IgE- induced histamine secretion in rat peritoneal mast cells. 2. RHC 80267, 10 microM and R59 022, 50 microM both enhanced OAG-induced histamine release by 30% and 40% respectively. 3. In the concentration range 3-30 microM, R59 022 enhanced anti-IgE-induced histamine release by up to about 40%, whereas RHC 80267 was without effect. 4. The enhancement of anti-IgE-induced histamine release by R59 022 is consistent with a role for protein kinase C in transducing immunological signals to rat peritoneal mast cells. 5. The lack of effect of RHC 80267 in this situation may indicate that in the mast cell, DAG kinase is more active than DAG lipase in degrading physiological levels of DAG.
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PMID:The actions of inhibitors of diacylglycerol kinase and diacylglycerol lipase on histamine release from rat peritoneal mast cells. 244 87

Using the double whole-cell patch-clamp technique, we determined that dialysis of cell pairs by GTP[S] potentiated electrical uncoupling induced by extracellular addition of carbamylcholine (CCh). An inhibitor of diglyceride lipase, RHC 80267, further potentiated CCh/GTP[S]-induced junctional channel closure, probably by accumulation of diacylglycerol. Moreover, the protein kinase C inhibitor polymyxin B completely blocked uncoupling elicited by CCh/GTP[S]. These results provide the first evidence suggesting that gap junction channel closure by cholinergic stimulation is mediated by a G-protein, which acts by increasing phosphatidylinositol biphosphate breakdown and protein kinase C activity.
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PMID:A G-protein mediates secretagogue-induced gap junctional channel closure in pancreatic acinar cells. 248 Sep 14

RHC 80267, on inhibitor of diacylglycerol lipase, was used to investigate the role of diacylglycerol in acid secretion by isolated rat gastric parietal cells. Unexpectedly, RHC 80267 stimulated the production of inositol phosphates in [3H]inositol-prelabeled cells and increased levels of 32P-labeled phosphatidic acid to the same degree as did carbachol. RHC 80267 increased diacylglycerol to a greater extent than did carbachol, and additionally decreased levels of [3H]arachidonic acid. This suggests that RHC 80267 stimulated phospholipase C and inhibited diacylglycerol lipase in parietal cells. RHC inhibited [14C]aminopyrine uptake, a measure of acid secretion, stimulated by carbachol or by simultaneous addition of carbachol and dibutyryl-cAMP. These data support the model that the diacylglycerol/protein kinase C branch of the phosphoinositide system is inhibitory to acid secretion.
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PMID:Stimulation of inositol phosphate and diacylglycerol production by RHC 80267, a diacylglycerol-lipase inhibitor, in rat gastric parietal cells: effects on hydrogen ion secretion. 253 97

Angiogenin stimulates capillary and umbilical vein endothelial cell prostacyclin secretion but not that of prostaglandins of the E series. The response was quantitated by radioimmunoassay and by [3H]arachidonate labeling followed by analysis of the secreted prostaglandins. The stimulated secretion lasts for several minutes and is optimal at 2-4 min. The dose-response (peak at 1-10 ng/ml) is similar to that previously observed for activation of endothelial cell phospholipase C. Stimulated secretion was blocked by pretreatment with the inhibitors of prostacyclin synthesis, indomethacin and tranylcypromine, and also the specific inhibitor of phospholipase A2, quinacrine, as well as pertussis toxin and the diglyceryl and monoglyceryl lipase inhibitor RHC 80267. Stimulated secretion was also abolished in cells that were either pretreated for 48 hr with phorbol ester to down-regulate protein kinase C or incubated with the protein kinase inhibitor H7. Hydrolysis of phosphatidylinositol by phospholipase A2 appears to be the source of angiogenin-mobilized arachidonate; angiogenin-induced hydrolysis of phosphatidylcholine was not detected. Activation of phospholipase A2 occurs in the absence of an angiogenin-induced calcium flux. The results are discussed in terms of mechanisms of agonist-induced intracellular arachidonate mobilization and relevance to angiogenesis.
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PMID:Angiogenin stimulates endothelial cell prostacyclin secretion by activation of phospholipase A2. 264 38


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