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Vol. 19, Issue 12, 5593-5603, December 2008

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Ca²⁺-regulated Pool of Phosphatidylinositol-3-phosphate Produced by Phosphatidylinositol 3-Kinase C2 on Neurosecretory Vesicles

Peter J. Wen^*, Shona L. Osborne^*, Isabel C. Morrow, Robert G. Parton, Jan Domin, and Frederic A. Meunier^*

*Molecular Dynamics of Synaptic Function Laboratory, Queensland Brain Institute and School of Biomedical Sciences, The University of Queensland, St. Lucia, 4072 Queensland, Australia; Centre for Microscopy and Microanalysis and Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia; and Renal Section, Faculty of Medicine, Imperial College, London W12 0NN, United Kingdom

Submitted June 12, 2008; Revised September 15, 2008; Accepted September 30, 2008
Monitoring Editor: Sean Munro

Phosphatidylinositol-3-phosphate [PtdIns(3)P] is a key player in early endosomal trafficking and is mainly produced by class III phosphatidylinositol 3-kinase (PI3K). In neurosecretory cells, class II PI3K-C2 and its lipid product PtdIns(3)P have recently been shown to play a critical role during neuroexocytosis, suggesting that two distinct pools of PtdIns(3)P might coexist in these cells. However, the precise characterization of this additional pool of PtdIns(3)P remains to be established. Using a selective PtdIns(3)P probe, we have identified a novel PtdIns(3)P-positive pool localized on secretory vesicles, sensitive to PI3K-C2 knockdown and relatively resistant to wortmannin treatment. In neurosecretory cells, stimulation of exocytosis promoted a transient albeit large increase in PtdIns(3)P production localized on secretory vesicles sensitive to PI3K-C2 knockdown and expression of PI3K-C2 catalytically inactive mutant. Using purified chromaffin granules, we found that PtdIns(3)P production is controlled by Ca²⁺. We confirmed that PtdIns(3)P production from recombinantly expressed PI3K-C2 is indeed regulated by Ca²⁺. We provide evidence that a dynamic pool of PtdIns(3)P synthesized by PI3K-C2 occurs on secretory vesicles in neurosecretory cells, demonstrating that the activity of a member of the PI3K family is regulated by Ca²⁺ in vitro and in living neurosecretory cells.

Address correspondence to: Frederic A. Meunier (f.meunier{at}uq.edu.au).

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