Kinsella Jackie M, Laidlaw Hilary A, Tang Teresa, Harvey Jenni, Sutherland Calum, Ashford Michael L J
Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
BMC Pharmacol. 2004 Aug 24;4:17. doi: 10.1186/1471-2210-4-17.
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.
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.
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.
3-胍基丙酸衍生物可减轻肥胖糖尿病小鼠的体重。我们评估了这些类似物之一，即氨基胍羧酸盐BVT.12777，是否通过与瘦素相同的机制在大鼠胰岛素瘤细胞中打开ATP敏感性钾通道（KATP通道）。
BVT.12777通过激活KATP通道使CRI-G1大鼠胰岛素瘤细胞超极化。相比之下，BVT.12777并未直接激活异源表达的胰腺β细胞KATP亚基。尽管BVT.12777刺激了丝裂原活化蛋白激酶（MAPK）和信号转导子与转录激活子3（STAT3）的磷酸化，但对磷脂酰肌醇-3-激酶（PI3K）下游的酶没有影响。BVT.12777对CRI-G1细胞中KATP的激活不依赖于MAPK或PI3K活性。共聚焦成像显示BVT.12777诱导了细胞肌动蛋白的重新组织。此外，已证明BVT.12777在CRI-G1细胞中对KATP的激活依赖于肌动蛋白细胞骨架动力学，这与瘦素的情况相似。
本研究表明，BVT.12777与瘦素一样，可激活胰岛素瘤细胞中的KATP通道。与瘦素不同的是，BVT.12777以不依赖PI3K的方式激活KATP通道，但与瘦素一样，通道激活依赖于肌动蛋白细胞骨架重塑。因此，BVT.12777似乎至少在KATP通道激活方面起到了瘦素模拟物的作用，并且可能绕过瘦素途径的上游信号成分。
