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)

The benzophenanthridine alkaloid chelerythrine is a potent, selective antagonist of the Ca++/phospholopid-dependent protein kinase (Protein kinase C: PKC) from the rat brain. Half-maximal inhibition of the kinase occurs at 0.66 microM. Chelerythrine interacted with the catalytic domain of PKC, was a competitive inhibitor with respect to the phosphate acceptor (histone IIIS) (Ki = 0.7 microM) and a non-competitive inhibitor with respect to ATP. This effect was further evidenced by the fact that chelerythrine inhibited native PKC and its catalytic fragment identically and did not affect [3H]- phorbol 12,13 dibutyrate binding to PKC. Chelerythrine selectively inhibited PKC compared to tyrosine protein kinase, cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase. The potent antitumoral activity of celerythrine measured in vitro might be due at least in part to inhibition of PKC and thus suggests that PKC may be a model for rational design of antitumor drugs.
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PMID:Chelerythrine is a potent and specific inhibitor of protein kinase C. 224 23

Modulation of protein kinase C (PKC) activity in basophils (B) can influence IgE-mediated histamine release (HR). The present study investigated the effects of chelerythrine, which inhibits isolated PKC (IC50 0.7 microM), on different activation pathways in B. Fc epsilon RI-mediated HR was strongly inhibited by chelerythrine (86.5 +/- 5.4%, 5 microM, n = 11). TPA-induced mediator release was also suppressed: 77.1 +/- 8.5% inhibition (7.5 microM). HR due to non-immunological stimuli (A23187, FMLP) was strongly inhibited by chelerythrine. Previously, other selective PKC-inhibitors have been shown to potentiate IgE-mediated HR from B suggesting a negative modulatory role of PKC, whereas non-specific inhibitors such as staurosporine inhibited HR. Chelerythrine might therefore be less selective for PKC. This may be indicated by the fact that chelerythrine inhibits PKC at its catalytic domain, which is homologous with other protein kinases.
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PMID:Investigations with the selective PKC inhibitor chelerythrine on human basophils. 752 60

Consecutive challenges with thyrotropin-releasing hormone (TRH) of oocytes expressing the TRH receptor (TRH-R) resulted in a pronounced desensitization, manifested as a decrease in chloride current amplitude and an increase in response latency. Exposure to low concentrations of TRH resulted in a marked decrease in the amplitude of the subsequent response to a higher concentration of the agonist, even though the second challenge was given before the onset of the response to the first challenge (within 3 - 15 s). Cellular calcium concentration ([Ca]i) did not increase within this interval, suggesting that calcium was not involved in the desensitization process. The latency of the second response, however, was either unchanged or shortened, implying additive effects of processes initiated by the first challenge. A longer interval (30 s) between the two challenges brought about a more pronounced decrease in amplitude and a prolongation of response latency. The calcium mobilization initiated by a second challenge with a high concentration of the agonist exhibited a longer latency, a lower rate of [Ca]i increase and a lower amplitude. Stimulation of co-expressed cholinergic-muscarinic ml receptors with a low concentration of acetylcholine resulted in a pronounced desensitization of the TRH response (heterologous desensitization). Activation of protein kinase C by beta-phorbol 12-myristate, 13-acetate resulted in a dose-dependent inhibition of the response to TRH, suggesting that protein kinase C was involved in desensitization. Chelerythrine, a specific inhibitor of protein kinase C, abolished a large part of the desensitization. A mutant of the TRH-R that lacks protein kinase C consensus phosphorylation sites in the C-terminal region, exhibited desensitization.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Desensitization of the response to thyrotropin-releasing hormone in Xenopus oocytes is an amplified process that precedes calcium mobilization. 753 27

Chelerythrine (CHELE), a specific, potent protein kinase C (PKC) inhibitor, disrupts memory formation for a one-trial peck-avoidance task. Three predictions were made about how CHELE, injected into chick brain near the time of training, would affect memory formation, based on previous work with two classes of protein kinase inhibitors (M. R. Rosenzweig et al., 1992; P. A. Serrano et al., 1994) and the in vitro inhibition of PKC by CHELE: (a) CHELE, injected into the intermediate medial hyperstriatum ventrale, would significantly impair memory formation; (b) the amnestic dose would be approximately 10 nmol; (c) CHELE would not produce amnesia for about 45 min after training, but significantly impair memory by 60 min. Experimental tests confirmed each prediction. This study adds to evidence that PKC activity is part of a cascade of neurochemical events initiated by learning and that PKC activity shortly after training is necessary for long-term memory.
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PMID:Protein kinase C inhibitor chelerythrine disrupts memory formation in chicks. 761 17

Using grease gap recordings, age-related changes in serotonin2A receptors were assessed in sensorimotor regions of the cortex by examining serotonin-induced facilitation of the N-methyl-D-aspartate depolarization in cortical wedges prepared from young adult (3-6 months) and senescent (22-34 months) Fisher 344 rats. Serotonin (10-100 microM) facilitated the N-methyl-D-aspartate depolarization in wedges from young adult rats in a concentration-dependent manner, whereas no facilitation was observed in wedges from senescent rats. Similar results were obtained when +/- 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, a mixed serotonin2A and serotonin2C receptor agonist, was substituted for serotonin. In contrast, agonists at alpha 1A-adrenoceptors, metabotropic glutamate receptors and muscarinic cholinoceptors facilitated the N-methyl-D-aspartate depolarization in wedges from both young adult and senescent rats. Chelerythrine and staurosporine, inhibitors of protein kinase C, but not concanavalin A, myo-inositol or calmodulin antagonists, restored the serotonin facilitation in wedges from senescent animals. In situ hybridization histochemistry revealed that serotonin2A receptor messenger RNA was present in layers II-VI of the cortex, with the highest density of silver grains located in layers III and V of both young adult and senescent rats. Detailed examination of layer V showed that silver grains were significantly higher than background only over pyramidal cells. We conclude that serotonin2A receptors are expressed by pyramidal cells in both young adult and senescent rats and that serotonin acts directly on these receptors to facilitate the N-methyl-D-aspartate depolarization. Moreover, in senescent rats, signal transduction at cortical serotonin2A receptors involved with facilitation of the N-methyl-D-aspartate response is compromised as a result of protein kinase C activation.
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PMID:Loss of cortical serotonin2A signal transduction in senescent rats: reversal following inhibition of protein kinase C. 765 16

1. The mouse AtT-20/D16-16 anterior pituitary tumour cell line was used as a model system for the study of phorbol 12-myristate 13-acetate (PMA)-mediated enhancement of calcium-evoked adrenocorticotrophin (ACTH) secretion. 2. PMA stimulated ACTH secretion from intact cells in a concentration-dependent manner. Other phorbol esters; phorbol 12,13-dibutyrate (PDBu) and phorbol 12,13-didecanoate (PDD) and diacylglycerol analogues; 1-oleoyl-2-acetyl-sn-glycerol (OAG) and 1,2-dioctanoyl-sn-glycerol (DOG) also stimulated ACTH release from intact AtT-20 cells. This would suggest that activation of protein kinase C (PKC) stimulates ACTH secretion from AtT-20 cells. 3. Calcium stimulated ACTH secretion from electrically-permeabilized cells over the concentration-range of 10(-7) M to 10(-5) M. PMA (10(-7) M) enhanced the amount of ACTH secreted at every concentration of calcium investigated. The PKC inhibitor, chelerythrine (10(-5) M) blocked the PMA (10(-7) M)-evoked enhancement of calcium (10(-5) M)-stimulated ACTH secretion but did not alter significantly the calcium (10(-5) M)-evoked secretion itself. This suggests that PKC modulates the secretory response to increases in intracellular calcium but does not mediate the effects of calcium. 4. Guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S, 10(-5) M) stimulated ACTH secretion from permeabilized cells in the absence of calcium and was additive with calcium-evoked ACTH secretion up to a maximum value which could be achieved by calcium acting alone. This suggests that a GTP-binding protein mediates the secretory response to increases in the intracellular calcium. PMA (10-7 M) enhanced ACTH secretion stimulated by the combination of calcium and GTP-gamma-S (10-5 M).5. GTP-gamma-S stimulated ACTH secretion from permeabilized cells in a concentration-dependent manner with a threshold of 10-6 M. PMA (10-7 M) increased the amount of ACTH secretion evoked by every concentration of GTP-gamma-S investigated. Chelerythrine (10-s M) blocked the PMA (10-7 M)-evoked enhancement of GTP-gamma-S (10-4 M)-stimulated ACTH secretion but did not significantly alter GTP-gamma-S(10-4 M)-evoked secretion itself. This suggests that PKC modulates the secretory response to GTP-gamma-S but does not mediate the effects of GTP-gamma-S.6. GTP-gamma-S (10-8-10-4-M) stimulated ACTH secretion from permeabilized cells either in the presence or absence of ATP (5 mM) indicating that its effects on secretion are ATP-independent.7. The results of the present study support the hypothesis that, in AtT-20 cells, PMA is acting at some site distal to calcium entry which modulates the ability of an increase in cytosolic calcium concentration to stimulate ACTH secretion. This site of action is either at the level of or at some stage distal to a GTP-binding protein which mediates the effects of calcium upon secretion.8. PMA, unlike adenosine 3':5'-cyclic monophosphate (cyclic AMP) (Guild, 1991), can stimulate ACTH secretion from permeabilized cells in the absence of added calcium and guanine nucleotides which suggests that PMA and cyclic AMP are acting through distinct mechanisms at this post calcium site of action.
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PMID:Effects of protein kinase C activators upon the late stages of the ACTH secretory pathway of AtT-20 cells. 781 8

We have investigated phospholipase D (PLD) activation in rat parotid acini prelabeled with [14C]stearic acid. In the presence of 2% ethanol, muscarinic and alpha-adrenergic agonists stimulated the formation of [14C]phosphatidylethanol as a result of a PLD activity. The calcium ionophore, ionomycin, and the phorbol esters, 4 beta-phorbol 12-myristate 13-acetate (PMA) and phorbol 12,13-dibutyrate (PDBu), also stimulated phosphatidylethanol accumulation, but 1-oleyl-2-acetyl-sn-glycerol (OAG), a permeant analogue of diacylglycerol did not. Chelerythrine and staurosporine, two inhibitors of protein kinase C, failed to affect any response. These results suggest that protein kinase C was not involved in the regulation of PLD activity. A difference between PLD regulation by PMA and receptor-mediated agonists was observed with regard to the extracellular calcium requirement. Our results strongly suggest that PLD activation in parotid acini involved different pathways: a calcium-dependent pathway activated by receptor-mediated agonists and a calcium-independent pathway activated by phorbol esters. Moreover, we observed that PLD activation did not result in any change in phosphatidic acid level. We propose that the phosphatidyl transferase activity of PLD reflected a metabolic pathway which may allow a base-exchange reaction in parotid gland.
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PMID:Receptor- and phorbol ester-mediated phospholipase D activation in rat parotid involves two different pathways. 790 6

Aromatic L-amino acid decarboxylase (AAAD) is required for the synthesis of catecholamines, serotonin, and the trace amines. We found that the protein kinase C activator phorbol 12-myristate 13-acetate administered intracerebroventricularly transiently increased AAAD activity by 30-50% over control values within approximately 30 min in the striatum and midbrain of the mouse. The enzyme increase was manifested as an apparent increase of Vmax with little change of Km for either L-3,4-dihydroxyphenylalanine or pyridoxal phosphate. Chelerythrine, a protein kinase C inhibitor, prevented the phorbol ester-induced increase of AAAD. Moreover, okadaic acid, a serine/threonine-selective protein phosphatase 1 and 2A inhibitor, also increased AAAD activity in the mouse striatum and midbrain. Taken together, these observations suggest that protein kinase C-mediated pathways modulate AAAD activity in vivo.
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PMID:Phorbol ester administration transiently increases aromatic L-amino acid decarboxylase activity of the mouse striatum and midbrain. 803 93

The present study investigated whether protein kinase C (PKC) plays a role in ischemic preconditioning in the rat heart. Chelerythrine, a specific antagonist of PKC, and 1,2-dioctanoyl-sn-glycerol (DOG), a diacylglycerol analogue and specific antagonist of PKC, were used to determine whether preconditioning could be blocked or triggered, respectively. Sprague-Dawley rats were anesthetized and instrumented for coronary occlusion and reperfusion. All animals were subjected to 45 minutes of regional ischemia (ISC) followed by 2.5 hours of reperfusion. The preconditioning protocol consisted of 5 minutes of ischemia and then 10 minutes of reperfusion. There were six groups: (1) control (group C, n = 5), (2) preconditioned and ISC (group PC, n = 6), (3) chelerythrine given 2 minutes before ISC (group CC, n = 5), (4) preconditioned and chelerythrine given 2 minutes before ISC (group PCC, n = 6), (5) DOG (dissolved in dimethylsulfoxide [DMSO]) given 10 minutes before ISC (group CD, n = 5), and (6) DMSO given 10 minutes before ISC (group DMSO, n = 3). The end point was infarct size measured using triphenyl tetrazolium chloride and expressed as a percentage of the volume at risk (I/R), measured with fluorescent particles. I/R was significantly reduced by preconditioning (group C, 58.6 +/- 5.0%; group PC, 32.7 +/- 6.3%; P < .01) and by the PKC agonist DOG, which reduced I/R to a similar extent as preconditioning (group C, 58.6 +/- 5.0%; group CD, 28.0 +/- 7.0%; P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase C. Its role in ischemic preconditioning in the rat. 806 29

Endotoxin, interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) dose-dependently increased the expression of tissue factor and at the same time induced thrombomodulin down-regulation on the surface of cultured bovine aortic endothelial cells. Chelerythrine, a selective protein kinase C inhibitor, strongly reduced endotoxin-, IL1 beta- and TNF alpha-induced tissue factor expression but remained without effect with regard to thrombomodulin down-regulation measured in parallel. On the contrary, staurosporine, a highly potent, non-selective PKC inhibitor, simultaneously abolished tissue factor expression and thrombomodulin down-regulation induced by endotoxin, IL1 beta and TNF alpha. These results show that protein kinase C is deeply involved in the process leading to pyrogen-induced tissue factor expression and suggest that thrombomodulin down-regulation is regulated by a different pathway.
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PMID:Chelerythrine, a selective protein kinase C inhibitor, counteracts pyrogen-induced expression of tissue factor without effect on thrombomodulin down-regulation in endothelial cells. 813 8


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