HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Koster, J. C. Articles by Nichols, C. G. Search for Related Content PubMed PubMed Citation Articles by Koster, J. C. Articles by Nichols, C. G. Social Bookmarking                What's this?

ATP and Sulfonylurea Sensitivity of Mutant ATP-Sensitive K⁺ Channels in Neonatal Diabetes

Implications for Pharmacogenomic Therapy

From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri

The prediction that overactivity of the pancreatic ATP-sensitive K⁺ channel (K_ATP channel) underlies reduced insulin secretion and causes a diabetic phenotype in humans has recently been borne out by genetic studies implicating "activating" mutations in the Kir6.2 subunit of K_ATP as causal in both permanent and transient neonatal diabetes. Here we characterize the channel properties of Kir6.2 mutations that underlie transient neonatal diabetes (I182V) or more severe forms of permanent neonatal diabetes (V59M, Q52R, and I296L). In all cases, the mutations result in a significant decrease in sensitivity to inhibitory ATP, which correlates with channel "overactivity" in intact cells. Mutations can be separated into those that directly affect ATP affinity (I182V) and those that stabilize the open conformation of the channel and indirectly reduce ATP sensitivity (V59M, Q52R, and I296L). With respect to the latter group, alterations in channel gating are also reflected in a functional "uncoupling" of sulfonylurea (SU) block: SU sensitivity of I182V is similar to that of wild-type mutants, but the SU sensitivity of all gating mutants is reduced, with the I296L mutant being resistant to block by tolbutamide (10 mmol/l). These results have important implications for the use of insulinotropic SU drugs as an alternative therapy to insulin injections.

Abbreviations: K_ATP channel, ATP-sensitive K⁺ channel; PIP₂, phosphatidylinositol 4,5-bisphosphate; PND, permanent neonatal diabetes; SU, sulfonylurea; TND, transient neonatal diabetes

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. Gach, K. Wyka, M. T. Malecki, A. Noczynska, J. Skupien, J. Nazim, M. Szalecki, J. Bodalski, J. Sieradzki, and W. Mlynarski Islet-Specific Antibody Seroconversion in Patients With Long Duration of Permanent Neonatal Diabetes Caused by Mutations in the KCNJ11 Gene Diabetes Care, August 1, 2007; 30(8): 2080 - 2082. [Full Text] [PDF]

				R. Masia, J. C. Koster, S. Tumini, F. Chiarelli, C. Colombo, C. G. Nichols, and F. Barbetti An ATP-Binding Mutation (G334D) in KCNJ11 Is Associated With a Sulfonylurea-Insensitive Form of Developmental Delay, Epilepsy, and Neonatal Diabetes Diabetes, February 1, 2007; 56(2): 328 - 336. [Abstract] [Full Text] [PDF]

				J. C. Koster, M. S. Remedi, R. Masia, B. Patton, A. Tong, and C. G. Nichols Expression of ATP-Insensitive KATP Channels in Pancreatic {beta}-Cells Underlies a Spectrum of Diabetic Phenotypes Diabetes, November 1, 2006; 55(11): 2957 - 2964. [Abstract] [Full Text] [PDF]

				A. I. Tarasov, H. J. Welters, S. Senkel, G. U. Ryffel, A. T. Hattersley, N. G. Morgan, and F. M. Ashcroft A Kir6.2 Mutation Causing Neonatal Diabetes Impairs Electrical Activity and Insulin Secretion From INS-1 {beta}-Cells Diabetes, November 1, 2006; 55(11): 3075 - 3082. [Abstract] [Full Text] [PDF]

				E. R. Pearson, I. Flechtner, P. R. Njolstad, M. T. Malecki, S. E. Flanagan, B. Larkin, F. M. Ashcroft, I. Klimes, E. Codner, V. Iotova, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N. Engl. J. Med., August 3, 2006; 355(5): 467 - 477. [Abstract] [Full Text] [PDF]

				C.-W. Lin, Y.-W. Lin, F.-F. Yan, J. Casey, M. Kochhar, E. B. Pratt, and S.-L. Shyng Kir6.2 Mutations Associated With Neonatal Diabetes Reduce Expression of ATP-Sensitive K+ channels: Implications in Disease Mechanism and Sulfonylurea Therapy Diabetes, June 1, 2006; 55(6): 1738 - 1746. [Abstract] [Full Text] [PDF]

				J. C. Koster, M. A. Permutt, and C. G. Nichols Diabetes and Insulin Secretion: The ATP-Sensitive K+ Channel (KATP) Connection Diabetes, November 1, 2005; 54(11): 3065 - 3072. [Abstract] [Full Text] [PDF]