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標題: Serine-385 phosphorylation of inwardly rectifying K(+) channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the K(ATP) channel and insulin secretion in rats
作者: Chang, T.J.
Chen, W.P.
Yang, C.
Lu, P.H.
Liang, Y.C.
Su, M.J.
Lee, S.C.
Chuang, L.M.
關鍵字: AMP-activated protein kinase;Insulin secretion;K(ATP) channel;Serine;phosphorylation;Rosiglitazone;beta-cell function;sensitive potassium channels;activated;receptor-gamma;pancreatic-islets;phosphatidylinositol 3-kinase;peroxisome proliferator;troglitazone cs-045;signaling pathways;diabetes-mellitus;gene-expression
Project: Diabetologia
期刊/報告no:: Diabetologia, Volume 52, Issue 6, Page(s) 1112-1121.
Rosiglitazone, an insulin sensitiser, not only improves insulin sensitivity but also enhances insulin secretory capacity by ameliorating gluco- and lipotoxicity in beta cells. Rosiglitazone can stimulate insulin secretion at basal and high glucose levels via a phosphatidylinositol 3-kinase (PI3K)-dependent pathway. We hypothesised that regulation of phosphorylation of the ATP-sensitive potassium (K(ATP)) channel might serve as a key step in the regulation of insulin secretion. Insulin secretory responses were studied in an isolated pancreas perfusion system, cultured rat islets and MIN6 and RINm5F beta cells. Signal transduction pathways downstream of PI3K were explored to link rosiglitazone to K(ATP) channel conductance with patch clamp techniques and insulin secretion measured by ELISA. Rosiglitazone stimulated AMP-activated protein kinase (AMPK) activity and induced inhibition of the K(ATP) channel conductance in islet beta cells; both effects were blocked by the PI3K inhibitor LY294002. Following stimulation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a pharmacological activator, both AICAR-stimulated insulin secretion and inhibition of K(ATP) channel conductance were unaffected by LY294002, indicating that AMPK activation occurs at a site downstream of PI3K activity. The serine residue at amino acid position 385 of Kir6.2 was found to be the substrate phosphorylation site of AMPK when activated by rosiglitazone or AICAR. Our data indicate that PI3K-dependent activation of AMPK is required for rosiglitazone-stimulated insulin secretion in pancreatic beta cells. Phosphorylation of the Ser(385) residue of the Kir6.2 subunit of the K(ATP) channel by AMPK may play a role in insulin secretion.
ISSN: 0012-186X
DOI: 10.1007/s00125-009-1337-4
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