Phorbol Ester TPA- and Bradykinin-Induced Arachidonic Acid Release from Keratinocytes Is Catalyzed by a Cytosolic Phospholipase A2(cPLA2)
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Tetradecanoylphorbol Acetate
Bradykinin receptor
Phospholipase A
Inositol trisphosphate
Phorbol
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Bradykinin receptor
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Inositol trisphosphate
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The effects of protein kinase C activation on phospholipase A2 and phospholipase C activity in permeabilised cultured myometrial cells from guinea pig uterus have been studied. Phospholipase A2 activity was followed by measurement of [3H]arachidonic acid release from [3H]arachidonic acid-prelabelled membrane lipids. [3H]Arachidonic acid release was stimulated by Ca2+ at 1-10 microM and by GTP gamma S at 1 microM to 1 mM in the presence of 10 microM Ca2+. The activation by calcium was enhanced 89.5 +/- 12.7% (P < 0.01) in the presence of 1 microM phorbol 12-myristate 13-acetate (PMA) and that by 1 microM GTP gamma S by 65.4 +/- 4.4% (P < 0.001). The PMA enhancement of arachidonic acid release was completely blocked by 3 microM staurosporine. Phospholipase C activation was followed by measurement of [3H]inositol polyphosphate production from [3H]inositol-prelabelled membrane lipids. This was stimulated by Ca2+ at 0.1 and 10 microM and by 1 and 50 microM GTP gamma S. PMA at 1 microM caused a consistent reduction in the extent of Ca2+ and GTP gamma S-stimulated inositol polyphosphate production and 3 microM reversed the inhibitory action of PMA. The data are consistent with arachidonic acid release in permeabilised myometrial cells from guinea pigs reflecting in large part phospholipase A2 activation and with that pathway being stimulated by protein kinase C activation. They are also consistent with protein kinase C activation causing reduction in phospholipase C pathways in uterine myocytes, at least as measured by inositol polyphosphate release.
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Inositol trisphosphate
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Phospholipase A
Phorbol
Tetradecanoylphorbol Acetate
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Journal Article Phospholipase activity in skin after application of phorbol esters and 3-methylcholanthrene Get access Edward Bresnick, Edward Bresnick Search for other works by this author on: Oxford Academic PubMed Google Scholar Glenn Bailey, Glenn Bailey Search for other works by this author on: Oxford Academic PubMed Google Scholar Robert J. Bonney, Robert J. Bonney 1Merck Institute for Therapeutic ResearchRahway, NJ 07065, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Paul Wightman Paul Wightman 1Merck Institute for Therapeutic ResearchRahway, NJ 07065, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Carcinogenesis, Volume 2, Issue 11, 1981, Pages 1119–1122, https://doi.org/10.1093/carcin/2.11.1119 Published: 01 January 1981 Article history Published: 01 January 1981 Received: 26 May 1981 Accepted: 08 September 1981
Methylcholanthrene
Phospholipase A
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Tetradecanoylphorbol Acetate
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The effect of various phospholipase A 2 and protein kinase inhibitors on the arachidonic acid liberation in bovine platelets induced by the protein kinase activator 12‐O‐tetradecanoylphorbol–13‐acetate (TPA) was studied. TPA stimulates arachidonic acid release mainly by activating group IV cytosolic PLA 2 (cPLA 2 ), since inhibitors of this enzyme markedly inhibited arachidonic acid formation. However, group VI Ca 2+ ‐independent PLA 2 (iPLA 2 ) seems to contribute to the arachidonic acid liberation too, since the relatively specific iPLA 2 inhibitor bromoenol lactone (BEL) decreased arachidonic acid generation in part. The pronounced inhibition of the TPA‐induced arachidonic acid release by the protein kinase C (PKC) inhibitors GF 109203X and Ro 31–82220, respectively, and by the p38 MAP kinase inhibitor SB 202190 suggests that the activation of the PLA 2 s by TPA is mediated via PKC and p38 MAP kinase.
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We reported that protein kinase C (PKC) inhibitors increase the release of arachidonic acid induced by fluoroaluminate (AlF 4 − ), an unspecific G‐protein activator, in intact human platelets. Now we demonstrate that this effect is independent of the extracellular Ca 2+ concentration and that AlF 4 − ‐induced release of AA is abolished by BAPTA, an intracellular Ca 2+ chelator, even in the presence of GF 109203X, a specific and potent PKC inhibitor. This compound also blocks the liberation of the secretory phospholipase A 2 in the extracellular medium, indicating that this enzyme is not involved in the potentiation of arachidonic acid by PKC inhibitors. On the other hand, the latter effect is completely abolished by treatment of platelets with AACOCF 3 , a specific inhibitor of cytosolic phospholipase A 2 (cPLA 2 ). These observations indicate that cPLA 2 is responsible for the AlF 4 − ‐induced release of arachidonic acid by a mechanism that is down‐regulated by PKC.
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Bradykinin receptor
Second messenger system
Inositol phosphate
Phosphoinositide phospholipase C
Inositol trisphosphate
Diacylglycerol lipase
Gq alpha subunit
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We studied the effect of endotoxin on bradykinin-induced inositol 1,4,5-triphosphate (IP3) production and the relationship between IP3 and phospholipase A2 or thromboxane A2. When exposed with 0.1, 1.0, and 10 microg ml(-1) lipopolysaccharide (LPS) for short-term (60 min), 100 nmol L(-1) bradykinin-induced IP3 production was stimulated in a dose-dependent manner from 569.2+/-42.4 in absence of LPS to 714.3+/-52.8, 804.5+/-42.6, and 894.1+/-62.6 pmol mg protein(-1). Treatment of 100 micromol L(-1) ACA (a phospholipase A2 inhibitor) and 10 micromol L(-1) BM13.177 (a thromboxane A2 inhibitor) significantly decreased bradykinin-induced IP3 production and LPS (1.0 microg mL(-1)) modulation of bradykinin-induced IP3 formation from 804.5+/-42.6 to 217.4+/-12.7 and 208.6+/-17.1 pmol mg protein(-1), respectively. LPS modulation of bradykinin-induced IP3 production was significantly blocked by 1 micromol L(-1) TMB-8 (an intracellular Ca2+ antagonist) from 804.5+/-42.6 to 507.8+/-33.4 pmol mg protein(-1). LPS modulation of bradykinin-induced IP3 production was significantly inhibited from 804.5+/-42.6 to 397.4+/-30.3 pmol mg protein(-1) by treatment of 10 micromol L(-1) indomethacin. In conclusion, short-term administration of LPS stimulates bradykinin-induced IP3 formation through activation of phospholipase A2 and thromboxane A2 and the stimulation is associated with an elevation of intracellular Ca2+.
Bradykinin receptor
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Inositol trisphosphate
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