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Vol. 16, Issue 10, 4841-4851, October 2005

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Phosphatidylinositol 3-Kinase C2 Is Essential for ATP-dependent Priming of Neurosecretory Granule Exocytosis

Frédéric A. Meunier ^* , Shona L. Osborne  , Gerald R.V. Hammond ^* , Frank T. Cooke , Peter J. Parker ^*, Jan Domin ^||, and Giampietro Schiavo ^*

^* Lincoln's Inn Fields Laboratories, London Research Institute, Cancer Research UK, London WC2A 3PX, United Kingdom; Molecular Dynamics of Synaptic Function Laboratory, School of Biomedical Sciences, University of Queensland, St. Lucia, 4072 Queensland, Australia; Biochemistry and Molecular Biology, University College London, WC1E 6BT London, United Kingdom; and ^|| Renal Section, Faculty of Medicine, Imperial College, London W12 0NN, United Kingdom

Submitted February 28, 2005; Revised June 16, 2005; Accepted July 14, 2005
Monitoring Editor: Keith Mostov

Neurotransmitter release and hormonal secretion are highly regulated processes culminating in the calcium-dependent fusion of secretory vesicles with the plasma membrane. Here, we have identified a role for phosphatidylinositol 3-kinase C2 (PI3K-C2) and its main catalytic product, PtdIns3P, in regulated exocytosis. In neuroendocrine cells, PI3K-C2 is present on a subpopulation of mature secretory granules. Impairment of PI3K-C2 function specifically inhibits the ATP-dependent priming phase of exocytosis. Overexpression of wild-type PI3K-C2 enhanced secretion, whereas transfection of PC12 cells with a catalytically inactive PI3K-C2 mutant or a 2xFYVE domain sequestering PtdIns3P abolished secretion. Based on these results, we propose that production of PtdIns3P by PI3K-C2 is required for acquisition of fusion competence in neurosecretion.

Abbreviations used: PI3K, phosphatidylinositol 3-kinase; PtdIns(4,5)P₂, phosphatidylinositol-4,5-bisphosphate; Syt I, synaptotagmin 1; EEA1, early endosomal antigen 1; LDCV, large dense core vesicles; hGH, human growth hormone.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

These authors contributed equally to this work.

Address correspondence to: Giampietro Schiavo (giampietro.schiavo{at}cancer.org.uk) or Frederic A. Meunier (f.meunier{at}uq.edu.au).

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