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PROTEIN AND VESICLE TRAFFICKING, CYTOSKELETON
Department of Biochemistry and Molecular Biology, Center for Diabetes Research, Indiana University School of Medicine, Indianapolis, Indiana 46202
Submitted 6 March 2003 ; accepted in final form 18 May 2003
Glucose-stimulated insulin granule exocytosis in pancreatic 
-cells
involves cortical actin remodeling that results in the transient disruption of
the interaction between polymerized actin with the plasma membrane t-SNARE
(target membrane soluble N-ethylmaleimide-sensitive factor attachment
protein receptor) complex. To examine the mechanism underlying the initiation
of cortical actin remodeling, we have used the actin nucleating/stabilizing
agent jasplakinolide to show that remodeling is initiated at a step proximal
to the ATP-sensitive K+ channels in the stimulus-secretion pathway.
Confocal immunofluorescent microscopy revealed that cortical actin remodeling
was required for glucose-stimulated insulin secretion. Furthermore, glucose
was found to mediate the endogenous activation state of the Rho family GTPase
Cdc42, a positive proximal effector of actin polymerization, resulting in a
net decrease of Cdc42-GTP within 5 min of stimulation. Intriguingly, glucose
stimulation resulted in the rapid and reversible glucosylation of Cdc42,
suggesting that glucose inactivated Cdc42 by selective glucosylation to induce
cortical actin rearrangement. Moreover, expression of the constitutively
active form of Cdc42 (Q61L) inhibited glucose-stimulated insulin secretion,
whereas the dominant negative form (T17N) was without effect, suggesting that
glucose-stimulated insulin secretion requires Cdc42 cycling to the GDP-bound
state. In contrast, KCl-stimulated insulin secretion was unaffected by the
expression of dominant negative or constitutively active Cdc42 and ceased to
modulate endogenous Cdc42 activation, consistent with glucose-dependent
cortical actin remodeling. These findings reveal that glucose regulates the
cortical actin network through modulation of Cdc42 cycling to induce insulin
secretion in pancreatic -cells.
jasplakinolide; glucosylation; syntaxin; insulin granule; exocytosis
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