title: Control of secretory granule access to the plasma membrane by PI3 kinase-γ.
abstract: The role and mechanism of phosphatidylinositol 3-OH (PI3) kinase as a regulator of insulin secretion is much debated. Studies employing non-selective pharmacological agents suggest a negative role for this key signal transduction enzyme in insulin release, perhaps through regulation of ATP-sensitive K (+) channels. There are however, three PI3 kinase families containing several kinase isoforms. More recent studies, including our own recently published work, have begun to investigate PI3 kinase isoform-specific mechanisms regulating insulin secretion. Building on our previous work demonstrating that mice lacking a G-protein coupled PI3 kinase catalytic subunit (p110γ -/-) lack first phase insulin secretion and display a blunted second phase of secretion, we have now elucidated the mechanism by which this PI3 kinase isoform acts as a positive regulator of insulin secretion. Using a combined molecular and pharmacological approach, together with biophysical assays of insulin exocytosis and cellular imaging, we demonstrated that p110γ is an important modulator of insulin granule exocytosis and localization to the plasma membrane by modulating cortical actin density.
authors.affiliation: Alberta Diabetes Institute and Department of Pharmacology University of Alberta, Edmonton, AB Canada. pmacdonald@pmcol.ualberta.ca
authors.forename: Patrick
authors.initials: P
authors.lastname: MacDonald
mesh_terms: D000199:Actins / Q000378:metabolism / Q000502:physiology; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005089:Exocytosis / Q000235:genetics* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D051381:Rats; D022142:Secretory Vesicles / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000199:Actins; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse