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Regulated Expression of Adenosine Triphosphate-Sensitive Potassium Channel Subunits in Pancreatic ß-Cells¹

Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Joel F. Habener, M.D., Laboratory of Molecular Endocrinology, Massachusetts General Hospital, 55 Fruit Street, WEL320, Boston, Massachusetts 02114. E-mail: jhabener{at}partners.org

The regulation of glucose-dependent insulin secretion in pancreatic ß-cells is linked to the expression and function of the ATP-sensitive potassium channel (K_ATP), which is composed of a sulfonylurea receptor (SUR1) and an inwardly rectifying potassium channel (Kir6.2). Previous animal and human genetic studies have demonstrated that disruption or defective expression of K_ATP subunit genes has a profound impact on the regulation of insulin secretion. Little is known about how SUR1 and Kir6.2 gene expression is regulated. Here we show that high glucose concentrations lead to a marked decrease (70%) in Kir6.2 messenger RNA (mRNA) levels in isolated rat pancreatic islets as well as in the INS-1 ß-cell line. This effect is reversible, because exposure to low glucose reinduces Kir6.2 transcript levels. The cognate K_ATP channel subunit SUR1 showed similar down-regulation at high glucose concentration. The K_ATP channel activity of INS-1 cells cultivated at high glucose was reduced by 33–51%. In contrast, glucagon-like peptide-1 (GLP-1) induced Kir6.2 mRNA steady state levels and was able to prevent glucose-dependent inhibition of Kir6.2 mRNA and K_ATP channel activity. To provide further insight into the mechanisms by which glucose and GLP-1 regulate ß-cell K_ATP channel genes, we have cloned and initiated the characterization of the Kir6.2 gene transcriptional regulatory regions contained within the entire 4.5 kb flanked by the SUR1 and Kir6.2 genes. Transient transfection experiments with five deletion constructs in a pancreatic ß-cell line (INS-1) showed that the proximal 988 bp of the Kir6.2 promoter sequence contributes only 25–30% to the total basal promoter activity. The minimal promoter region -67/+140, also encompassing parts of the 5'-untranslated region, confers sensitivity to GLP-1, which stimulates transcriptional activity of the Kir6.2 minigene by about 2-fold. We propose that glucose- and GLP-1-dependent regulation of K_ATP subunit genes may be important in the adaptation of ß-cells to changes in secretory demands in physiological and diseased states.

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