Regulation of Insulin Secretion by Phosphatidylinositol‐4,5‐Bisphosphate
Copyright policy )Regulation of Insulin Secretion by Phosphatidylinositol‐4,5‐Bisphosphate
Abstract The role of PIP2 in pancreatic beta cell function was examined here using the beta cell line MIN6B1. Blocking PIP2 with PH‐PLC‐GFP or PIP5KIγ RNAi did not impact on glucose‐stimulated secretion although susceptibility to apoptosis was increased. Over‐expression of PIP5KIγ improved cell survival and inhibited secretion with accumulation of endocytic vacuoles containing F‐actin, PIP2, transferrin receptor, caveolin 1, Arf6 and the insulin granule membrane protein phogrin but not insulin. Expression of constitutively active Arf6 Q67L also resulted in vacuole formation and inhibition of secretion, which was reversed by PH‐PLC‐GFP co‐expression. PIP2 co‐localized with gelsolin and F‐actin, and gelsolin co‐expression partially reversed the secretory defect of PIP5KIγ‐over‐expressing cells. RhoA/ROCK inhibition increased actin depolymerization and secretion, which was prevented by over‐expressing PIP5KIγ, while blocking PIP2 reduced constitutively active RhoA V14‐induced F‐actin polymerization. In conclusion, although PIP2 plays a pro‐survival role in MIN6B1 cells, excessive PIP2 production because of PIP5KIγ over‐expression inhibits secretion because of both a defective Arf6/PIP5KIγ‐dependent endocytic recycling of secretory membrane and secretory membrane components such as phogrin and the RhoA/ROCK/PIP5KIγ‐dependent perturbation of F‐actin cytoskeleton remodelling.
- Imperial College London United Kingdom
- Albert Einstein College of Medicine United States
- Yeshiva University United States
- University of Geneva Switzerland
- University of Lausanne Switzerland
Electrophoresis, Phosphatidylinositol 4,5-Diphosphate/antagonists & inhibitors/ physiology, Phosphotransferases (Alcohol Group Acceptor)/antagonists &, Phosphatidylinositol 4,5-Diphosphate, Cell Survival, Blotting, Western, Inhibitors/ biosynthesis, Cell Culture Techniques, Apoptosis, Endocytosis/drug effects, Fluorescence, Cell Line, Mice, Insulin-Secreting Cells, 616, Insulin Secretion, In Situ Nick-End Labeling, Animals, Insulin, Insulin-Secreting Cells/drug effects/enzymology/pathology/ secretion, Animals; Apoptosis/drug effects; Blotting, Western; Cell Culture Techniques; Cell Line; Cell Survival/drug effects; Electrophoresis, Polyacrylamide Gel; Endocytosis/drug effects; Glucose/pharmacology; In Situ Nick-End Labeling; Insulin/secretion; Insulin-Secreting Cells/drug effects; Insulin-Secreting Cells/enzymology; Mice; Microscopy, Confocal; Microscopy, Fluorescence; Phosphatidylinositol 4,5-Diphosphate/antagonists & inhibitors; Phosphatidylinositol 4,5-Diphosphate/physiology; Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors; Phosphotransferases (Alcohol Group Acceptor)/biosynthesis; Protein Transport; Vacuoles/drug effects; Vacuoles/enzymology, Vacuoles/drug effects/enzymology/metabolism, Microscopy, Polyacrylamide Gel, Microscopy, Confocal, Blotting, Apoptosis/drug effects, 0601 Biochemistry And Cell Biology, Glucose/pharmacology, Endocytosis, Phosphotransferases (Alcohol Group Acceptor), Protein Transport, Glucose, Microscopy, Fluorescence, Confocal, Vacuoles, Electrophoresis, Polyacrylamide Gel, Insulin/ secretion, Western, Cell Survival/drug effects, Developmental Biology, ddc: ddc:616
Electrophoresis, Phosphatidylinositol 4,5-Diphosphate/antagonists & inhibitors/ physiology, Phosphotransferases (Alcohol Group Acceptor)/antagonists &, Phosphatidylinositol 4,5-Diphosphate, Cell Survival, Blotting, Western, Inhibitors/ biosynthesis, Cell Culture Techniques, Apoptosis, Endocytosis/drug effects, Fluorescence, Cell Line, Mice, Insulin-Secreting Cells, 616, Insulin Secretion, In Situ Nick-End Labeling, Animals, Insulin, Insulin-Secreting Cells/drug effects/enzymology/pathology/ secretion, Animals; Apoptosis/drug effects; Blotting, Western; Cell Culture Techniques; Cell Line; Cell Survival/drug effects; Electrophoresis, Polyacrylamide Gel; Endocytosis/drug effects; Glucose/pharmacology; In Situ Nick-End Labeling; Insulin/secretion; Insulin-Secreting Cells/drug effects; Insulin-Secreting Cells/enzymology; Mice; Microscopy, Confocal; Microscopy, Fluorescence; Phosphatidylinositol 4,5-Diphosphate/antagonists & inhibitors; Phosphatidylinositol 4,5-Diphosphate/physiology; Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors; Phosphotransferases (Alcohol Group Acceptor)/biosynthesis; Protein Transport; Vacuoles/drug effects; Vacuoles/enzymology, Vacuoles/drug effects/enzymology/metabolism, Microscopy, Polyacrylamide Gel, Microscopy, Confocal, Blotting, Apoptosis/drug effects, 0601 Biochemistry And Cell Biology, Glucose/pharmacology, Endocytosis, Phosphotransferases (Alcohol Group Acceptor), Protein Transport, Glucose, Microscopy, Fluorescence, Confocal, Vacuoles, Electrophoresis, Polyacrylamide Gel, Insulin/ secretion, Western, Cell Survival/drug effects, Developmental Biology, ddc: ddc:616
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