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J. Biol. Chem., Vol. 279, Issue 26, 27534-27541, June 25, 2004

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Phospholipase D1 Regulates Secretagogue-stimulated Insulin Release in Pancreatic -Cells^*

William E. Hughes, Recipient of a Fellowship from the Royal Society (UK) and a Howard Florey Fellowship from the NH&MRC, Australia, Zehra Elgundi, Ping Huang¶, Michael A. Frohman¶, and Trevor J. Biden

From the Cell Signalling Group, The Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia and the ^¶Department of Pharmacology and The Centre for Developmental Genetics, University Medical Centre at Stony Brook, Stony Brook, New York 11794

Phospholipase D (PLD) has been strongly implicated in the regulation of Golgi trafficking as well as endocytosis and exocytosis. Our aim was to investigate the role of PLD in regulating the biphasic exocytosis of insulin from pancreatic -cells that is essential for mammalian glucose homeostasis. We observed that PLD activity in MIN6 pancreatic -cells is closely coupled to secretion. Cellular PLD activity was increased in response to a variety of secretagogues including the nutrient glucose and the cholinergic receptor agonist carbamoylcholine. Conversely, pharmacological or hormonal inhibition of stimulated secretion reduced PLD activity. Most importantly, blockade of PLD-catalyzed phosphatidic acid formation using butan-1-ol inhibited insulin secretion in both MIN6 cells and isolated pancreatic islets. It was further established that PLD activity was required for both the first and the second phase of glucose-stimulated insulin release, suggesting a role in the very distal steps of exocytosis, beyond granule recruitment into a readily releasable pool. Visualization of granules using green fluorescent protein-phogrin confirmed a requirement for PLD prior to granule fusion with the plasma membrane. PLD1 was shown to be the predominant isoform in MIN6 cells, and it was located at least partially on insulin granules. Overexpression of wild-type or a dominant negative catalytically inactive mutant of PLD1 augmented or inhibited secretagogue-stimulated secretion, respectively. The results suggest that phosphatidic acid formation on the granule membrane by PLD1 is essential for the regulated secretion of insulin from pancreatic -cells.

Received for publication, March 18, 2004 , and in revised form, April 5, 2004.

^* This work was supported by funding from the National Health and Medical Research Council (Australia). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. E-mail: w.hughes{at}garvan.org.au.

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