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MBC in Press, published online ahead of print July 29, 2005
Mol. Biol. Cell 10.1091/mbc.E05-02-0171

A more recent version of this article appeared on October 1, 2005
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Submitted on February 28, 2005
Revised on June 16, 2005
Accepted on July 14, 2005

PI3-Kinase C2{alpha} Is Essential for ATP-dependent Priming of Neurosecretory Granule Exocytosis

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

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

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 PI3-kinase C2{alpha} (PI3K-C2{alpha}) and its main catalytic product, PtdIns3P, in regulated exocytosis. In neuroendocrine cells, PI3K-C2{alpha} is present on a subpopulation of mature secretory granules. Impairment of PI3K-C2{alpha} function specifically inhibits the ATP-dependent priming phase of exocytosis. Overexpression of wild-type PI3K-C2{alpha} enhanced secretion, while transfection of PC12 cells with a catalytically-inactive PI3K-C2{alpha} mutant or a 2xFYVE domain sequestering PtdIns3P abolished secretion. Based on these results, we propose that production of PtdIns3P by PI3K-C2{alpha} is required for acquisition of fusion competence in neurosecretion.

{ddagger}These authors contributed equally to this work.

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




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