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doi: 10.1242/10.1242/jcs.00083
Research Article |
1 Department of Biochemistry, School of Medical Sciences, University of Bristol,
University Walk, Bristol BS8 1TD, UK
2 School of Biological Sciences, University of Manchester, 2.205 Stopford
Building, Oxford Road, Manchester M13 9PT, UK
* Author for correspondence (e-mail: g.a.rutter{at}bris.ac.uk)
Accepted 2 August 2002
Recruitment of secretory vesicles to the cell surface is essential for the sustained secretion of insulin in response to glucose. At present, the molecular motors involved in this movement, and the mechanisms whereby they may be regulated, are undefined. To investigate the role of kinesin family members, we labelled densecore vesicles in clonal ß-cells using an adenovirally expressed, vesicle-targeted green fluorescent protein (phogrin.EGFP), and employed immunoadsorption to obtain highly purified insulin-containing vesicles. Whereas several kinesin family members were expressed in this cell type, only conventional kinesin heavy chain (KHC) was detected in vesicle preparations. Expression of a dominant-negative KHC motor domain (KHCmut) blocked all vesicular movements with velocity >0.4 µm second-1, which demonstrates that kinesin activity was essential for vesicle motility in live ß-cells. Moreover, expression of KHCmut strongly inhibited the sustained, but not acute, stimulation of secretion by glucose. Finally, vesicle movement was stimulated by ATP dose-dependently in permeabilized cells, which suggests that glucose-induced increases in cytosolic [ATP] mediate the effects of the sugar in vivo, by enhancing kinesin activity. These data therefore provide evidence for a novel mechanism whereby glucose may enhance insulin release.
Key words: Kinesin, Insulin, Exocytosis, Glucose, Islet, ß-cell, Pancreas
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