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 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 beta-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.
Kinsella
Jackie M
JM
Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. jackie_kinsella@hotmail.com
Laidlaw
Hilary A
HA
Tang
Teresa
T
Harvey
Jenni
J
Sutherland
Calum
C
Ashford
Michael L J
ML
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D007267:Injections / Q000379:methods; D007340:Insulinoma / Q000737:chemistry* / Q000201:enzymology / Q000473:pathology; D054086:KATP Channels; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009865:Oocytes / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000737:chemistry* / Q000201:enzymology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000008:administration & dosage / Q000378:metabolism*; D018075:RNA, Complementary / Q000008:administration & dosage; D051381:Rats; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014982:Xenopus laevis / Q000235:genetics; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000199:Actins; D006146:Guanidines; D054086:KATP Channels; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D019869:Phosphatidylinositol 3-Kinases; D024661:Potassium Channels, Inwardly Rectifying; D018075:RNA, Complementary; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C500387:BVT.12777; C092520:uK-ATP-1 potassium channel