| Autor: |
Pigeau, Gary M., Kolic, Jelena, Ball, Brandon J., Hoppa, Michael B., Wang, Ying W., Rückle, Thomas, Woo, Minna, Manning Fox, Jocelyn E., MacDonald, Patrick E. |
| Předmět: |
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| Zdroj: |
Diabetes; Sep2009, Vol. 58 Issue 9, p2084-2092, 9p, 7 Graphs |
| Abstrakt: |
OBJECTIVE--Phosphatidylinositol 3-OH kinase (PI3K) has a long-recognized role in β-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 PI3Kγ and its catalytic subunit p110γ in the regulation of insulin granule recruitment and exocytosis. RESEARCH DESIGN AND METHODS--The expression of p110γ was knocked down by small-interfering RNA, and p110γ 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 β-cells. Cortical F-actin was examined in INS-1 cells and human islets and in mouse β-cells lacking the phosphatase and tensin homolog (PTEN). RESULTS--Knockdown or inhibition of p110γ markedly blunted depolarization-induced insulin secretion and exocytosis and ablated the exocytotic response to direct Ca[sup 2+] infusion. This resulted from reduced granule localization to the plasma membrane and was associated with increased cortical F-actin. Inhibition of p110γ had no effect on F-actin in β-cells lacking PTEN. Finally, the effect of p110γ inhibition on granule localization and exocytosis could be rapidly reversed by agents that promote actin depolymerization. CONCLUSIONS--The G-protein-coupled PI3Kγ 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, p110γ activity plays an important role in maintaining a membrane-docked, readily releasable pool of secretory granules in insulinoma and human β-cells. Diabetes 58:2084-2092, 2009 [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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