Abstract
Background3-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.ResultsBVT.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.ConclusionsThis 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.
Highlights
ATP-sensitive K+ (KATP) channels are important regulators of cell function, coupling energy metabolism with electrical activity
Such an effect has been reported for leptin on CRI-G1 cells [13]
Application of the KATP channel inhibitor, tolbutamide (100 μM) during BVT.12777 exposure (Figure 2A) completely reversed the BVT.12777-induced hyperpolarization and decreased conductance, to -41.0 ± 4.8 mV (n = 5) and 0.58 ± 0.07 nS (n = 5) respectively, values indistinguishable from control (P > 0.05). These data indicate that BVT.12777 increases KATP current in this cell line
Summary
ATP-sensitive K+ (KATP) channels are important regulators of cell function, coupling energy metabolism with electrical activity. KATP channels are comprised of two proteins, derived from the sulphonylurea receptor (SUR) family and an inwardly rectifying K+ channel (Kir6.x family), the exact composition of these being dependent upon tissue [1,2]. Pancreatic β-cells and insulin-secreting clonal cell lines express KATP channels consisting of Kir6.2 and SUR1 subunits [3]. KATP channels are present in numerous tissues and are the target for drugs that inhibit or increase channel activity [4,5]. Modulation of KATP channel activity in pancreatic β-cells has profound effects on insulin secretion and glucose homeostasis [6]. Sulphonylureas such as tolbutamide and glibenclamide inhibit channel activity, resulting in β-cell (page number not for citation purposes)
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