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J. Biol. Chem., Vol. 278, Issue 52, 52042-52051, December 26, 2003

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5'-AMP-activated Protein Kinase Controls Insulin-containing Secretory Vesicle Dynamics^*

Takashi Tsuboi, Gabriela da Silva Xavier, Isabelle Leclerc, and Guy A. Rutter

From the Henry Wellcome Laboratories for Integrated Cell Signalling and Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, United Kingdom

Changes in 5'-AMP-activated protein kinase (AMPK) activity have recently been implicated in the control of insulin secretion by glucose (da Silva Xavier, G., Leclerc, I., Varadi, A., Tsuboi, T., Moule, S. K., and Rutter, G. A. (2003) Biochem. J. 371, 761–774). Here, we examine the possibility that activation of AMPK may regulate distal steps in insulin secretion, including vesicle movement and fusion with the plasma membrane. Vesicle dynamics were imaged in single pancreatic MIN6 -cells expressing lumen-targeted pH-insensitive yellow fluorescent protein, neuropeptide Y.Venus, or monomeric red fluorescent protein by total internal reflection fluorescence and Nipkow disc confocal microscopy. Overexpression of a truncated, constitutively active form of AMPK (AMPK1, 1–312, T172D; AMPK CA), inhibited glucose-stimulated (30 versus 3.0 mM) vesicle movements, and decreased the number of vesicles docked or fusing at the plasma membrane, while having no effect on the kinetics of individual secretory events. Expression of the activated form of AMPK also prevented dispersal of the cortical actin network at high glucose concentrations. Monitored in permeabilized cells, where the effects of AMPK CA on glucose metabolism and ATP synthesis were bypassed, AMPK CA inhibited Ca²⁺ and ATP-induced insulin secretion, and decreased ATP-dependent vesicle movements. These findings suggest that components of the vesicle transport network, including vesicle-associated motor proteins, may be targets of AMPK in -cells, dephosphorylation of which is required for vesicle mobilization at elevated glucose concentrations.

Received for publication, July 18, 2003 , and in revised form, October 1, 2003.

^* This work was supported in part by grants (to G. A. R.) from the Wellcome Trust (Project 062321; Programme 067081/Z/02/Z), the Biotechnology and Biological Sciences Research Council, the Human Frontiers Science Program, and Diabetes UK. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains QuickTime movies corresponding to panels D and E of Fig. 4 and panels E-G of Fig. 8.

Recipient of a Wellcome Trust advanced fellowship.

Recipient of a Wellcome Trust research leave fellowship. To whom correspondence should be addressed: Dept. of Biochemistry, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, United Kingdom. Tel.: 44-117-954-6401; Fax: 44-117-928-8274; E-mail: g.a.rutter{at}bristol.ac.uk.

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