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Am J Physiol Endocrinol Metab (March 18, 2003). doi:10.1152/ajpendo.00086.2003
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Submitted on February 24, 2003
Accepted on March 11, 2003

Cytoplasmic phospholipase A2-mediated formation of arachidonic acid and lysophospholipids are required for Ca2+-dependent exocytosis in mouse pancreatic {beta}-cells

Kirstine Juhl1, Marianne Hoy1, Hervor L. Olsen1, Krister Bokvist2, Alexander M. Efanov2, Else K. Hoffmann3, and Jesper Gromada2*

1 Laboratory of Islet Cell Physiology, Novo Nordisk A/S, Bagsvaerd, Denmark
2 Laboratory of Islet Cell Physiology, Novo Nordisk A/S, Bagsvaerd, Denmark; Department of Beta Cell Biology, Lilly Research Laboratories, Hamburg, Germany
3 Department of Biological Chemistry, The August Krogh Institute, University of Copenhagen, Copenhagen, Denmark

* To whom correspondence should be addressed. E-mail: gromada_jesper{at}lilly.com.

Using capacitance measurements, we investigated the effects of intracellularly applied recombinant human cytosolic phospholipase A2 (cPLA2{alpha}) and its lipolytic products arachidonic acid and lysophosphatidylcholine on Ca2+-dependent exocytosis in single mouse pancreatic {beta}-cells. cPLA2{alpha} dose-dependently (EC50=86 nM) stimulated depolarization-evoked exocytosis by 450% without affecting the whole-cell Ca2+-current or cytoplasmic Ca2+ levels. The stimulatory effect involved priming of secretory granules as reflected by an increase in the size of the readily releasable pool of granules from 70-80 to 280-300. cPLA2{alpha}-stimulated exocytosis was antagonised by the specific cPLA2 inhibitor AACOCF3. Ca2+-evoked exocytosis was reduced by 40% in cells treated with AACOCF3 or antisense oligonucleotide against cPLA2{alpha}. The action of cPLA2{alpha} was mimicked by a combination of arachidonic acid and lysophosphatidylcholine (470% stimulation) where each compound alone doubled the exocytotic response. Priming of insulin-containing secretory granules has been reported to involve Cl- uptake through ClC-3 Cl- channels. Accordingly, the stimulatory action of cPLA2{alpha} was inhibited by the Cl- channel inhibitor DIDS and in cells pretreated with ClC-3 Cl- channel antisense oligonucleotides. We propose that cPLA2{alpha} plays an important role in controlling the rate of exocytosis in {beta}-cells. This effect of cPLA2{alpha} reflects an enhanced transgranular Cl- flux leading to an increase in the number of granules available for release and requires the combined actions of arachidonic acid and lysophosphatidylcholine.




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