Glucose regulates the cortical actin network through modulation of Cdc42 cycling to stimulate insulin secretion

Angela K. Nevins, Debbie C. Thurmond

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Glucose-stimulated insulin granule exocytosis in pancreatic β-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 β-cells.

Original languageEnglish
JournalAmerican Journal of Physiology - Cell Physiology
Volume285
Issue number3 54-3
StatePublished - Sep 1 2003

Fingerprint

Actins
Modulation
Insulin
Glucose
SNARE Proteins
jasplakinolide
Chemical activation
rho GTP-Binding Proteins
Confocal microscopy
Excipients
Secretory Pathway
GTP Phosphohydrolases
Exocytosis
Cell membranes
Guanosine Triphosphate
Confocal Microscopy
Polymerization
Membrane Proteins
Adenosine Triphosphate
Cell Membrane

Keywords

  • Exocytosis
  • Glucosylation
  • Insulin granule
  • Jasplakinolide
  • Syntaxin

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Glucose regulates the cortical actin network through modulation of Cdc42 cycling to stimulate insulin secretion. / Nevins, Angela K.; Thurmond, Debbie C.

In: American Journal of Physiology - Cell Physiology, Vol. 285, No. 3 54-3, 01.09.2003.

Research output: Contribution to journalArticle

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