title: Phosphatidylinositol 3-kinase C2alpha is essential for ATP-dependent priming of neurosecretory granule exocytosis.
abstract: 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 C2alpha (PI3K-C2alpha) and its main catalytic product, PtdIns3P, in regulated exocytosis. In neuroendocrine cells, PI3K-C2alpha is present on a subpopulation of mature secretory granules. Impairment of PI3K-C2alpha function specifically inhibits the ATP-dependent priming phase of exocytosis. Overexpression of wild-type PI3K-C2alpha enhanced secretion, whereas transfection of PC12 cells with a catalytically inactive PI3K-C2alpha mutant or a 2xFYVE domain sequestering PtdIns3P abolished secretion. Based on these results, we propose that production of PtdIns3P by PI3K-C2alpha is required for acquisition of fusion competence in neurosecretion.
authors.affiliation: Lincoln's Inn Fields Laboratories, London Research Institute, Cancer Research UK, London WC2A 3PX, United Kingdom.
authors.forename: Frédéric A
authors.initials: FA
authors.lastname: Meunier
authors.forename: Shona L
authors.initials: SL
authors.lastname: Osborne
authors.forename: Gerald R V
authors.initials: GR
authors.lastname: Hammond
authors.forename: Frank T
authors.initials: FT
authors.lastname: Cooke
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Parker
authors.forename: Jan
authors.initials: J
authors.lastname: Domin
authors.forename: Giampietro
authors.initials: G
authors.lastname: Schiavo
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000311:Adrenal Glands / Q000166:cytology; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000502:physiology; D058541:Class II Phosphatidylinositol 3-Kinases; D005089:Exocytosis / Q000502:physiology*; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009489:Neurosecretion / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D051381:Rats; D022142:Secretory Vesicles / Q000502:physiology*
chemical_list: D002395:Catecholamines; D018129:Phosphatidylinositol Phosphates; C055525:phosphatidylinositol 3-phosphate; D019382:Human Growth Hormone; D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D058541:Class II Phosphatidylinositol 3-Kinases