title: Activation of hypothalamic ATP-sensitive K+ channels by the aminoguanidine carboxylate BVT.12777.
abstract: Derivatives of 3-guanidinopropionic acid, such as leptin, reduce body weight in obese, diabetic mice. We have assessed whether one of these analogues, BVT.12777 activates intracellular signalling pathways in the arcuate nucleus in a manner analogous to leptin and insulin. In addition, because these hormones have been shown to activate K(ATP) channels in a subset of arcuate neurones, we examined whether this channel is also a functional endpoint for BVT.12777 in the arcuate nucleus. BVT.12777 transiently increased phosphorylation of MAPK, STAT3, PKB and GSK3, in a manner identical to that observed for leptin and insulin. BVT.12777 also hyperpolarized glucose-responsive neurones by increasing the activity of K(ATP) channels. The increase in K(ATP) activity driven by BVT.12777 was PI3-kinase independent, unlike leptin and insulin activation of this channel, and could also be elicited in isolated patches. However, K(ATP) activity induced by BVT.12777 was dependent on actin filament dynamics, both in intact neurones and isolated patches. Thus, BVT.12777 modulates arcuate neurone K(ATP) activity by re-organization of the cytoskeleton, a mechanism that has also been ascribed to leptin and insulin. Consequently, BVT.12777 appears to act as a leptin and insulin mimetic with respect to at least some elements of arcuate neurone intracellular signalling and the activation of K(ATP) channels. Resistance to leptin and insulin, associated with obesity has, at least in part, been postulated to be due to aberrant intracellular signalling in arcuate neurones. The data presented here indicate that it may be possible to develop drugs, which by-pass up-stream signalling components associated with adiposity hormone resistance, such as PI3-kinase, but can still induce functional outputs from arcuate neurones by targeting downstream components of the leptin and insulin signalling cascades.
authors.affiliation: Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
authors.forename: S
authors.initials: S
authors.lastname: Mirshamsi
authors.forename: H A
authors.initials: HA
authors.lastname: Laidlaw
authors.forename: D
authors.initials: D
authors.lastname: Spanswick
authors.forename: M L J
authors.initials: ML
authors.lastname: Ashford
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000187:drug effects / Q000378:metabolism; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism
chemical_list: C500387:BVT.12777; D004268:DNA-Binding Proteins; D020536:Enzyme Activators; D006146:Guanidines; D007328:Insulin; C510692:Kcnj1 protein, rat; D020738:Leptin; D024661:Potassium Channels, Inwardly Rectifying; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; D048370:MAP Kinase Kinase 2