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Research ArticleArticle

Pardaxin, a New Pharmacological Tool to Stimulate the Arachidonic Acid Cascade in PC12 Cells

Saleh Abu-Raya, Eugenia Bloch-Shilderman, Esther Shohami, Victoria Trembovler, Yechiel Shai, Joseph Weidenfeld, Saul Yedgar, Yehuda Gutman and Philip Lazarovici
Journal of Pharmacology and Experimental Therapeutics December 1998, 287 (3) 889-896;
Saleh Abu-Raya
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Eugenia Bloch-Shilderman
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Esther Shohami
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Victoria Trembovler
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Yechiel Shai
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Joseph Weidenfeld
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Saul Yedgar
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Yehuda Gutman
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Philip Lazarovici
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Abstract

The effect of Pardaxin, a neurotoxin that induces neurotransmitter release from neurons, on the arachidonic acid (AA) cascade was studied in PC12 cells. Both native and the synthetic Pardaxin selectively stimulated phospholipase A2 (PLA2) activity (measured by [3H]AA release) in the presence as well as in the absence of extracellular calcium. Pardaxin-stimulated PLA2 activity was also evident in the increased formation of lysophosphatidylcholine. Pardaxin analogs, lacking the α-helical structure that is essential for insertion into the plasma membrane, were ineffective in stimulating the AA cascade in PC12 cells. Pardaxin stimulation of PLA2 was markedly inhibited by the nonselective PLA2 inhibitors bromophenacyl bromide and mepacrine, by methyl arachidonyl fluorophosphonate, a dual inhibitor of calcium-dependent cytosolic PLA2 and the calcium-independent PLA2 and by bromoenol lactone[(E)-6-(bromoethylene)tetrahydro-3-(1-naphthalenyl-2H-pyran-2-one], a highly specific inhibitor of calcium-independent PLA2. After Pardaxin treatment, there was increased release of AA metabolites produced by the cyclooxygenase pathway as expressed in an 8-fold increase of PGE2 release. The release of other eicosanoids, such as 6-keto-PGF1α and thromboxane B2, was also augmented. Pardaxin-induced PGE2 release was observed in calcium-free medium and in the absence of any increase in cytosolic calcium. Dexamethasone partially inhibited Pardaxin-induced PGE2 release. This effect was reversed by the type II corticosteroid receptor antagonist RU-38486. Our results indicate that Pardaxin stimulates release of AA and eicosanoids, independently of calcium, and suggest that calcium-independent PLA2 plays an important role in Pardaxin stimulation of the AA cascade.

Footnotes

  • Send reprint requests to: Lazarovici Philip, Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, Hebrew University, P.O.B. 12065, Jerusalem, 91120, Israel.

  • ↵1 This study was supported in part by the David R. Bloom Center for Pharmacy at the Hebrew University.

  • ↵2 Present address: Department of Membrane Research and Biophysics, Weizmann Institute of Science, Rehovot, 76100, Israel.

  • ↵3 Present address: Department of Neurology, Hadassah University Hospital, P.O.B. 12000, Jerusalem, 91120, Israel.

  • ↵4 Present address: Department of Biochemistry, Faculty of Medicine, The Hebrew University, P.O.B. 12065, Jerusalem, 91120, Israel.

  • Abbreviations:
    AA
    arachidonic acid
    PLA2
    phospholipase A2
    iPLA2
    calcium-independent phospholipase A2
    PLC
    phospholipase C
    PLD
    phospholipase D
    PA
    phosphatidic acid
    PC
    phosphatidylcholine
    LPC
    lysophosphatidylcholine
    PI
    phosphatidylinositol
    PS
    phosphatidylserine
    Fura 2-AM
    acetoxymethyl ester of fura 2
    PGE2-prostaglandin E2
    TXB2, thromboxane B2
    DMEM
    Dulbecco’s modified Eagle’s medium
    Dex
    dexamethasone
    PBS
    phosphate-buffered saline
    EGTA
    ethyleneglycol-bis-(β-amino-ethyl ether) N,N′-tetra acetic acid
    PMSF
    phenylmethanesulfonyl
    RIA
    radioimmunoassay
    [Ca]i
    cytosolic calcium
    pBPB-4
    bromophenacyl bromide
    [Ca]o
    extracellular calcium
    BSA
    bovine serum albumin
    DAG
    diacylglycerol
    RHC-80267
    1,6-di[o-(carbamoyl)cyclohexaneoxim]hexane
    BEL
    bromoenol lactone[(E)-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one]
    MAFP
    methyl arachidonyl fluorophosphonate
    TLC
    thin-layer chromatography
    • Received September 30, 1997.
    • Accepted July 7, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 3
1 Dec 1998
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Research ArticleArticle

Pardaxin, a New Pharmacological Tool to Stimulate the Arachidonic Acid Cascade in PC12 Cells

Saleh Abu-Raya, Eugenia Bloch-Shilderman, Esther Shohami, Victoria Trembovler, Yechiel Shai, Joseph Weidenfeld, Saul Yedgar, Yehuda Gutman and Philip Lazarovici
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 889-896;

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Research ArticleArticle

Pardaxin, a New Pharmacological Tool to Stimulate the Arachidonic Acid Cascade in PC12 Cells

Saleh Abu-Raya, Eugenia Bloch-Shilderman, Esther Shohami, Victoria Trembovler, Yechiel Shai, Joseph Weidenfeld, Saul Yedgar, Yehuda Gutman and Philip Lazarovici
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 889-896;
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