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¹ Unité Propre de Recherche 2356, Centre National de la Recherche Scientifique, 67084 Strasbourg Cedex, France
² Department of Molecular Infectiology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
³ Department of Pharmacology and the Center for Developmental Genetics, University Medical Center at Stony Brook, Stony Brook, NY 11794

Address correspondence to Dr. Nicolas Vitale, Centre National de la Recherche Scientifique, Unité Propre de Recherche 2356, 5 rue Blaise Pascal, 67084 Strasbourg Cedex, France. Tel.: 33-388-45-67-12. Fax: 33-388-60-16-64. E-mail: vitalen{at}neurochem.u-strasbg.fr

The ADP ribosylation factor (ARF) GTP binding proteins are believed to mediate cytoskeletal remodeling and vesicular trafficking along the secretory pathway. Here we show that ARF6 is specifically associated with dense-core secretory granules in neuroendocrine PC12 cells. Stimulation with a secretagogue triggers the recruitment of secretory granules to the cell periphery and the concomitant activation of ARF6 by the plasma membrane-associated guanine nucleotide exchange factor, ARF nucleotide binding site opener (ARNO). Expression of the constitutively inactive ARF6(T27N) mutant inhibits secretagogue-dependent exocytosis from PC12 cells. Using a mutant of ARF6 specifically impaired for PLD1 stimulation, we find that ARF6 is functionally linked to phospholipase D (PLD)1 in the exocytotic machinery. Finally, we show that ARNO, ARF6, and PLD1 colocalize at sites of exocytosis, and we demonstrate direct interaction between ARF6 and PLD1 in stimulated cells. Together, these results provide the first direct evidence that ARF6 plays a role in calcium-regulated exocytosis in neuroendocrine cells, and suggest that ARF6-stimulated PLD1 activation at the plasma membrane and consequent changes in membrane phospholipid composition are critical for formation of the exocytotic fusion pore.

Key Words: ARF6; exocytosis; PC12 cells; phospholipase D; secretory granule

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