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

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 K(ATP )channels in rat insulinoma cells, by the same mechanism as leptin. RESULTS: BVT.12777 hyperpolarized CRI-G1 rat insulinoma cells by activation of K(ATP )channels. In contrast, BVT.12777 did not activate heterologously expressed pancreatic β-cell K(ATP )subunits directly. Although BVT.12777 stimulated phosphorylation of MAPK and STAT3, there was no effect on enzymes downstream of PI3K. Activation of K(ATP )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 K(ATP )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 K(ATP )channels in insulinoma cells. Unlike leptin, BVT.12777 activates K(ATP )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 K(ATP )channel activation, and may bypass up-stream signalling components of the leptin pathway.