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Open Access Research article

The aminoguanidine carboxylate BVT.12777 activates ATP-sensitive K+ channels in the rat insulinoma cell line, CRI-G1

Jackie M Kinsella, Hilary A Laidlaw, Teresa Tang, Jenni Harvey, Calum Sutherland and Michael LJ Ashford*

Author Affiliations

Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK

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BMC Pharmacology 2004, 4:17  doi:10.1186/1471-2210-4-17

Published: 24 August 2004

Abstract

Background

3-guanidinopropionic acid derivatives reduce body weight in obese, diabetic mice. We have assessed whether one of these analogues, the aminoguanidine carboxylate BVT.12777, opens KATP channels in rat insulinoma cells, by the same mechanism as leptin.

Results

BVT.12777 hyperpolarized CRI-G1 rat insulinoma cells by activation of KATP channels. In contrast, BVT.12777 did not activate heterologously expressed pancreatic β-cell KATP subunits directly. Although BVT.12777 stimulated phosphorylation of MAPK and STAT3, there was no effect on enzymes downstream of PI3K. Activation of KATP in CRI-G1 cells by BVT.12777 was not dependent on MAPK or PI3K activity. Confocal imaging showed that BVT.12777 induced a re-organization of cellular actin. Furthermore, the activation of KATP by BVT.12777 in CRI-G1 cells was demonstrated to be dependent on actin cytoskeletal dynamics, similar to that observed for leptin.

Conclusions

This study shows that BVT.12777, like leptin, activates KATP channels in insulinoma cells. Unlike leptin, BVT.12777 activates KATP channels in a PI3K-independent manner, but, like leptin, channel activation is dependent on actin cytoskeleton remodelling. Thus, BVT.12777 appears to act as a leptin mimetic, at least with respect to KATP channel activation, and may bypass up-stream signalling components of the leptin pathway.