help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Moritz, W.
Right arrow Articles by Habener, J. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Moritz, W.
Right arrow Articles by Habener, J. F.
Endocrinology Vol. 142, No. 1 129-138
Copyright © 2001 by The Endocrine Society

ARTICLES

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

Wolfgang Moritz2, Colin A. Leech, Jorge Ferrer3 and Joel F. Habener4

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 (KATP), 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 KATP 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 KATP channel subunit SUR1 showed similar down-regulation at high glucose concentration. The KATP 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 KATP channel activity. To provide further insight into the mechanisms by which glucose and GLP-1 regulate ß-cell KATP 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 KATP subunit genes may be important in the adaptation of ß-cells to changes in secretory demands in physiological and diseased states.




This article has been cited by other articles:


Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
S. Polakof, S. Panserat, E. Plagnes-Juan, and J. L. Soengas
Altered dietary carbohydrates significantly affect gene expression of the major glucosensing components in Brockmann bodies and hypothalamus of rainbow trout
Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2008; 295(4): R1077 - R1088.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
G. Kang, C. A. Leech, O. G. Chepurny, W. A. Coetzee, and G. G. Holz
Role of the cAMP sensor Epac as a determinant of KATP channel ATP sensitivity in human pancreatic {beta}-cells and rat INS-1 cells
J. Physiol., March 1, 2008; 586(5): 1307 - 1319.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
M. Acosta-Martinez and J. E. Levine
Regulation of KATP channel subunit gene expression by hyperglycemia in the mediobasal hypothalamus of female rats
Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1801 - E1807.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
F. Allagnat, D. Martin, D. F. Condorelli, G. Waeber, and J.-A. Haefliger
Glucose represses connexin36 in insulin-secreting cells
J. Cell Sci., November 15, 2005; 118(22): 5335 - 5344.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Minami, M. Yokokura, N. Ishizuka, and S. Seino
Normalization of Intracellular Ca2+ Induces a Glucose-responsive State in Glucose-unresponsive beta -Cells
J. Biol. Chem., July 5, 2002; 277(28): 25277 - 25282.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
M. Nakazaki, M. Kakei, H. Ishihara, N. Koriyama, H. Hashiguchi, K. Aso, M. Fukudome, Y. Oka, T. Yada, and C. Tei
Association of upregulated activity of KATP channels with impaired insulin secretion in UCP1-expressing insulinoma cells
J. Physiol., May 1, 2002; 540(3): 781 - 789.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2001 by The Endocrine Society