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Research ArticleCELLULAR AND MOLECULAR

Pardaxin Stimulation of Phospholipases A2 and Their Involvement in Exocytosis in PC-12 Cells

Eugenia Bloch-Shilderman, Saleh Abu-Raya, Victoria Trembovler, Hassia Boschwitz, Arie Gruzman, Michal Linial and Philip Lazarovici
Journal of Pharmacology and Experimental Therapeutics June 2002, 301 (3) 953-962; DOI: https://doi.org/10.1124/jpet.301.3.953
Eugenia Bloch-Shilderman
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Saleh Abu-Raya
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Victoria Trembovler
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Hassia Boschwitz
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Arie Gruzman
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Michal Linial
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Philip Lazarovici
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Abstract

Pardaxin (PX) is a voltage-dependent ionophore that stimulates catecholamine exocytosis from PC-12 pheochromocytoma cells both in the presence and absence of extracellular calcium. Using a battery of phospholipase A2 inhibitors we show that PX stimulation of phospholipase A2 (PLA2) enzymes is coupled with induction of exocytosis. We investigated the relationship between PX-induced PLA2 activity and neurotransmitter release by measuring the levels of arachidonic acid (AA), prostaglandin E2 (PGE2), and dopamine release. In the presence of extracellular calcium, the cytosolic PLA2inhibitor arachidonyl trifluoromethyl ketone (AACOCF3) inhibited by 100, 70, and 73%, respectively, the release of AA, PGE2, and dopamine induced by PX. The mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor 2′-amino-3′-methoxyflavone (PD98059) reduced by 100 and 82%, respectively, the release of AA and PGE2 induced by PX. In the absence of extracellular calcium, the calcium-independent PLA2 (iPLA2) inhibitors methyl arachidonyl fluorophosphonate, AACOCF3, and bromoenol lactone (BEL) inhibited by 80 to 90% PX stimulation of AA release, by 65 to 85% PX stimulation of PGE2 release, and by 80 to 90% PX-induced dopamine release. Using vesicle fusion-based enzyme-linked immunosorbent assay we found similar levels of inhibition of PX-induced exocytosis by these inhibitors. Also, PX induced the formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor complexes, an effect that was augmented byN-methylmaleimide. This complex formation was completely inhibited by BEL. Botulinum toxins type C1 and F significantly inhibited the release of AA, PGE2, and dopamine induced by PX. Our data suggest that PX stimulates exocytosis by activating cystolic PLA2 and iPLA2, leading to the generation of AA and eicosanoids, which, in turn, stimulate vesicle competence for fusion and neurotransmitter release.

Footnotes

  • ↵1 Current address: Hadassah Academic College, Haneviim Street 37, P.O. Box 1114, Jerusalem 91010, Israel.

  • E.B.-S. and S.A.-R. contributed equally to this work.

  • Abbreviations:
    SNARE
    solubleN-ethylmaleimide-sensitive factor attachment protein receptor (SNAP receptor)
    SNAP-25
    synaptosomal associated protein of 25 kDa
    VAMP
    vesicle-associated membrane protein (synaptobrevin)
    PX
    pardaxin
    AA
    arachidonic acid
    PLA2
    phospholipase A2
    sPLA2
    secretory phospholipase A2
    cPLA2
    cytosolic phospholipase A2
    iPLA2
    calcium-independent phospholipase A2
    MAPK
    mitogen-activated protein kinase
    AACOCF3
    arachidonyl trifluoromethyl ketone
    MAFP
    methyl arachidonyl fluorophosphonate
    BEL
    bromoenol lactone
    BSA
    bovine serum albumin
    NEM
    N-ethylmaleimide
    5-HETE
    5-hydroxyeicosatetraenoic acid
    HPLC
    high-pressure liquid chromatography
    DMEM
    Dulbecco's modified Eagle's medium
    ELISA
    enzyme-linked immunosorbent assay
    PBS
    phosphate-buffered saline
    RIA
    radioimmunoassay
    NGF
    nerve growth factor
    ERK
    extracellular regulated kinase
    PGE2
    prostaglandin E2
    NSF
    N-ethylmaleimide-sensitive factor
    BoNT/C1
    botulinum toxin type C1
    BoNT/F
    botulinum toxin type F
    O.D.
    optical density
    UO126
    1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio) butadiene
    PD98059
    2′-amino-3′-methoxyflavone
    • Received December 10, 2001.
    • Accepted February 27, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 3
1 Jun 2002
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Research ArticleCELLULAR AND MOLECULAR

Pardaxin Stimulation of Phospholipases A2 and Their Involvement in Exocytosis in PC-12 Cells

Eugenia Bloch-Shilderman, Saleh Abu-Raya, Victoria Trembovler, Hassia Boschwitz, Arie Gruzman, Michal Linial and Philip Lazarovici
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 953-962; DOI: https://doi.org/10.1124/jpet.301.3.953

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Research ArticleCELLULAR AND MOLECULAR

Pardaxin Stimulation of Phospholipases A2 and Their Involvement in Exocytosis in PC-12 Cells

Eugenia Bloch-Shilderman, Saleh Abu-Raya, Victoria Trembovler, Hassia Boschwitz, Arie Gruzman, Michal Linial and Philip Lazarovici
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 953-962; DOI: https://doi.org/10.1124/jpet.301.3.953
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