K252a, a new inhibitor of protein kinase C, concomitantly inhibits 40K protein phosphorylation and seroton in secretion in a phorbol ester-stimulated platelets

Yamada, Koji; Iwahashi, Kazuyuki; Kase, Hiroshi

doi:10.1016/s0006-291x(87)80471-0

Cited by 59 publications

(24 citation statements)

References 12 publications

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“…In line with this, blocking CaMKII with K252a resulted in increased oedema formation in the presence of PAF. It is of note that these results were obtained using 10 nM K252a, a concentration at which this inhibitor should not block other enzymes, such as PKA, MLCK and PKC [35,36]. Again, the present findings are in contrast to observations in endothelial monolayers, in which inhibition of CaMKII reduced thrombin-induced hyperpermeability [74].…”

Section: Discussioncontrasting

confidence: 92%

“…The phospholipase inhibitor edelfosine (L108) (Biomol, Hamburg, Germany; median inhibitory concentration (IC50) 10 mM [30], used at 30 mM) and the membrane-permeable IP3R antagonist xestospongin C (Biomol; IC50 0.4 mM [31], used at 1 mM) were prepared as stock solutions in ethanol, the MLCK inhibitor 5-iodonaphthalene-1-sulphonyl-homopiperazine (ML-7) (Biomol; IC50 0.3 mM [31], used at 35 mM) in 50% aqueous ethanol, and the ROCK inhibitor (+)-R-trans-4-(aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide (Y27632) (Tocris, Avonmouth, UK; IC50 0.8 mM [32,33], used at 10 mM) in dimethyl sulphoxide; aliquots from these stock solutions were added 10 min before PAF. The calmodulin-dependent protein kinase II (CaMKII) inhibitor K252a (Biomol; IC50 2 nM [34], used at 10 nM (IC50 for inhibition of protein kinase A (PKA), PKC and MLCK 20 nM [35,36])) was used to inhibit CaMKII. For the experiments on the role of extracellular Ca 2+ , the lungs were perfused with Krebs-Henseleit buffer containing different Ca 2+ concentrations from the beginning of the preparation.…”

Section: Methodsmentioning

confidence: 99%

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The inositol trisphosphate pathway mediates platelet-activating-factor-induced pulmonary oedema

Göggel¹

2005

Eur Respir J

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Platelet-activating factor (PAF) is a pro-inflammatory lipid mediator that increases vascular permeability by simultaneous activation of two pathways, one dependent on the cyclooxygenase metabolite prostaglandin E 2 and the other on the sphingomyelinase metabolite ceramide. The hypothesis that part of the PAF-induced oedema is mediated via the inositol 1,4,5-trisphosphate (IP 3 ) pathway or Rho kinase pathway was investigated.Oedema formation was induced in isolated perfused rat lungs by injection of 5 nmol PAF into the pulmonary artery. Lungs were pre-treated with specific inhibitors: edelfosine (L108) to block phosphatidyl-inositol-specific phospholipase C, xestospongin to block the IP 3 receptor, 5-iodonaphthalene-1-sulphonyl-homopiperazine (ML-7) to block myosin light chain kinase, and (+)-R-trans-4-(aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide (Y27632) to block Rho-associated protein kinase.Pre-treatment with L108 or xestospongin reduced PAF-induced oedema formation by 58 and 56%, respectively. The effect of L108 was additive to that of the cyclooxygenase inhibitor acetyl salicylic acid (88% oedema reduction). PAF-induced oedema formation was also reduced if extracellular calcium concentrations were lowered. Furthermore, treatment with ML-7 reduced oedema formation by 54%, whereas Y27632 was without effect.It is concluded that platelet-activating-factor-triggered oedema is mediated by activation of the inositol 1,4,5-trisphosphate pathway, influx of extracellular calcium and subsequent activation of a myosin light chain kinase-dependent and Rho-associated-protein-kinase-independent mechanism.

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Section: Discussioncontrasting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

The inositol trisphosphate pathway mediates platelet-activating-factor-induced pulmonary oedema

Göggel¹

2005

Eur Respir J

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“…More recent studies have indicated a more general action on kinases . Indeed, the recent information suggests that the compound inhibits kinases in a rather nonspecific way, by competing for ATP Yamada et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

K-252a: a specific inhibitor of the action of nerve growth factor on PC 12 cells

Koizumi¹,

Contreras²,

Matsuda³

et al. 1988

J. Neurosci.

321

207

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K-252a, a kinase inhibitor isolated from the culture broth of Nocardiopsis sp., selectively inhibits the actions of nerve growth factor (NGF) on PC 12 cells. At a concentration of 200 nM, K-252a prevents neurite generation initiated by NGF, but not neurite generation produced by fibroblast growth factor or outgrowth produced by dibutyryl cAMP. K-252a also inhibits the induction of ornithine decarboxylase by NGF, but stimulates ornithine decarboxylase induction by epidermal growth factor. Stimulation of phosphatidylinositol breakdown by NGF was similarly inhibited by K-252a, while stimulation by epidermal growth factor was enhanced. The NGF-induced decrease in the phosphorylation of a soluble protein, Nsp 100, was prevented by K- 252a. K-252a blocks the NGF-induced heterodown-regulation of the epidermal growth factor receptor, but not the epidermal growth factor- induced homodown-regulation of the epidermal growth factor receptor. K- 252a, then, provides a new tool for the dissection and study of NGF- requiring processes.

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“…[4][5][6][7] Multiple studies have shown that both increase in intracellular calcium and activation of protein kinase C (PKC) are required to mediate granule release. [8][9][10][11][12][13][14][15] Following platelet activation, tyrosine phosphorylation events of many proteins ensue. Multiple studies have shown that these tyrosine phosphorylation events are necessary for platelet signal transduction.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism and functional implications of thrombin-mediated tyrosine phosphorylation of PKCδ in platelets

Murugappan

Shankar

Bhamidipati

et al. 2005

Blood

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Thrombin has been known to cause tyrosine phosphorylation of protein kinase C ␦ (PKC␦) in platelets, but the molecular mechanisms and function of this tyrosine phosphorylation is not known. In this study, we investigated the signaling pathways used by protease-activated receptors (PARs) to cause tyrosine phosphorylation of PKC␦ and the role of this event in platelet function. PKC␦ was tyrosine phosphorylated by either PAR1 or PAR4 in a concentration-and time-dependent manner in human platelets. In particular, the

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K252a, a new inhibitor of protein kinase C, concomitantly inhibits 40K protein phosphorylation and seroton in secretion in a phorbol ester-stimulated platelets

Cited by 59 publications

References 12 publications

The inositol trisphosphate pathway mediates platelet-activating-factor-induced pulmonary oedema

The inositol trisphosphate pathway mediates platelet-activating-factor-induced pulmonary oedema

K-252a: a specific inhibitor of the action of nerve growth factor on PC 12 cells

Molecular mechanism and functional implications of thrombin-mediated tyrosine phosphorylation of PKCδ in platelets

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