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,1
* Department of Pharmacology, Oita University, Faculty of Medicine, Oita 879-5593, Japan;
Departments of Cell Pharmacology and
Anatomy, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan;
Division of Molecular Medicine, Center for Biomedical Science, Chiba University School of Medicine, Chiba 260-8670, Japan; and
¶ Department of Anatomy I, Fujita Health University School of Medicine, Toyoake 470-1192, Japan
Abstract
This study investigated mechanisms by which glucose increases readily releasable secretory granules via acting on preexocytotic steps, i.e., intracellular granule movement and granule access to the plasma membrane using a pancreatic ß-cell line, MIN6. Glucose-induced activation of the movement occurred at a substimulatory concentration with regard to insulin output. Glucose activation of the movement was inhibited by pretreatment with thapsigargin plus acetylcholine to suppress intracellular Ca2+ mobilization. Inhibitors of calmodulin and myosin light chain kinase also suppressed glucose activation of the movement. Simultaneous addition of glucose with Ca2+ channel blockers or the ATP-sensitive K+ channel opener diazoxide failed to suppress the traffic activation, and addition of these substances on top of glucose stimulation resulted in a further increase. Although stimulatory glucose had minimal changes in the intracellular granule distribution, inhibition of Ca2+ influx revealed increases by glucose of the granules in the cell periphery. In contrast, high K+ depolarization decreased the peripheral granules. Glucose-induced granule margination was abolished when the protein kinase C activity was downregulated. These findings indicate that preexocytotic control of insulin release is regulated by distinct mechanisms from Ca2+ influx, which triggers insulin exocytosis. The nature of the regulation by glucose may explain a part of potentiating effects of the hexose independent of the closure of the ATP-sensitive K+ channel.
Key Words: pancreatic ß-cell • granule mobilization • granule docking • myosin • novel protein kinase C
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