PMID- 19549714
OWN - NLM
STAT- MEDLINE
DCOM- 20090930
LR  - 20211020
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 58
IP  - 9
DP  - 2009 Sep
TI  - Insulin granule recruitment and exocytosis is dependent on p110gamma in 
      insulinoma and human beta-cells.
PG  - 2084-92
LID - 10.2337/db08-1371 [doi]
AB  - 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.
FAU - Pigeau, Gary M
AU  - Pigeau GM
AD  - Department of Pharmacology and the Alberta Diabetes Institute, University of 
      Alberta, Alberta, Canada.
FAU - Kolic, Jelena
AU  - Kolic J
FAU - Ball, Brandon J
AU  - Ball BJ
FAU - Hoppa, Michael B
AU  - Hoppa MB
FAU - Wang, Ying W
AU  - Wang YW
FAU - Ruckle, Thomas
AU  - Ruckle T
FAU - Woo, Minna
AU  - Woo M
FAU - Manning Fox, Jocelyn E
AU  - Manning Fox JE
FAU - MacDonald, Patrick E
AU  - MacDonald PE
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090623
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione)
RN  - 0 (Actins)
RN  - 0 (Calcium Channels)
RN  - 0 (Insulin)
RN  - 0 (Isoenzymes)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Quinoxalines)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Thiazolidinediones)
RN  - EC 2.7.1.137 (Class Ib Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.1.137 (PIK3CG protein, human)
RN  - EC 2.7.1.153 (Pik3cg protein, mouse)
SB  - IM
MH  - Actins/metabolism
MH  - Animals
MH  - Calcium Channels/physiology
MH  - Cell Line, Tumor
MH  - Class Ib Phosphatidylinositol 3-Kinase
MH  - Exocytosis/physiology
MH  - Humans
MH  - Insulin/*metabolism
MH  - Insulin Secretion
MH  - Insulin-Secreting Cells/*cytology/*metabolism
MH  - Insulinoma
MH  - Isoenzymes/genetics/metabolism
MH  - Membrane Potentials/physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Mutant Strains
MH  - Pancreatic Neoplasms
MH  - Patch-Clamp Techniques
MH  - Phosphatidylinositol 3-Kinases/genetics/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Quinoxalines/pharmacology
MH  - RNA, Small Interfering
MH  - Secretory Vesicles/*metabolism
MH  - Thiazolidinediones/pharmacology
PMC - PMC2731529
EDAT- 2009/06/25 09:00
MHDA- 2009/10/01 06:00
PMCR- 2010/09/01
CRDT- 2009/06/25 09:00
PHST- 2009/06/25 09:00 [entrez]
PHST- 2009/06/25 09:00 [pubmed]
PHST- 2009/10/01 06:00 [medline]
PHST- 2010/09/01 00:00 [pmc-release]
AID - db08-1371 [pii]
AID - 1371 [pii]
AID - 10.2337/db08-1371 [doi]
PST - ppublish
SO  - Diabetes. 2009 Sep;58(9):2084-92. doi: 10.2337/db08-1371. Epub 2009 Jun 23.