RGD Reference Report - Insulin granule recruitment and exocytosis is dependent on p110gamma in insulinoma and human beta-cells. - Rat Genome Database

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Insulin granule recruitment and exocytosis is dependent on p110gamma in insulinoma and human beta-cells.

Authors: Pigeau, GM  Kolic, J  Ball, BJ  Hoppa, MB  Wang, YW  Ruckle, T  Woo, M  Manning Fox, JE  MacDonald, PE 
Citation: Pigeau GM, etal., Diabetes. 2009 Sep;58(9):2084-92. Epub 2009 Jun 23.
RGD ID: 2324863
Pubmed: PMID:19549714   (View Abstract at PubMed)
PMCID: PMC2731529   (View Article at PubMed Central)
DOI: DOI:10.2337/db08-1371   (Journal Full-text)

OBJECTIVE: Phosphatidylinositol 3-OH kinase (PI3K) has a long-recognized role in beta-cell mass regulation and gene transcription and is implicated in the modulation of insulin secretion. The role of nontyrosine kinase receptor-activated PI3K isoforms is largely unexplored. We therefore investigated the role of the G-protein-coupled PI3Kgamma and its catalytic subunit p110gamma in the regulation of insulin granule recruitment and exocytosis. RESEARCH DESIGN AND METHODS: The expression of p110gamma was knocked down by small-interfering RNA, and p110gamma activity was selectively inhibited with AS605240 (40 nmol/l). Exocytosis and granule recruitment was monitored by islet perifusion, whole-cell capacitance, total internal reflection fluorescence microscopy, and electron microscopy in INS-1 and human beta-cells. Cortical F-actin was examined in INS-1 cells and human islets and in mouse beta-cells lacking the phosphatase and tensin homolog (PTEN). RESULTS: Knockdown or inhibition of p110gamma markedly blunted depolarization-induced insulin secretion and exocytosis and ablated the exocytotic response to direct Ca(2+) infusion. This resulted from reduced granule localization to the plasma membrane and was associated with increased cortical F-actin. Inhibition of p110gamma had no effect on F-actin in beta-cells lacking PTEN. Finally, the effect of p110gamma inhibition on granule localization and exocytosis could be rapidly reversed by agents that promote actin depolymerization. CONCLUSIONS: The G-protein-coupled PI3Kgamma is an important determinant of secretory granule trafficking to the plasma membrane, at least in part through the negative regulation of cortical F-actin. Thus, p110gamma activity plays an important role in maintaining a membrane-docked, readily releasable pool of secretory granules in insulinoma and human beta-cells.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Pik3cgRatsecretory granule localization  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pik3cg  (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit gamma)


Additional Information