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

ATP and Sulfonylurea Sensitivity of Mutant ATP-Sensitive K + Channels in Neonatal Diabetes Implications for Pharmacogenomic Therapy Joseph C. Koster , Maria S. Remedi , Crystal Dao and Colin G. Nichols From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri Address correspondence and reprint requests to Colin G. Nichols, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110. E-mail: cnichols{at}cellbio.wustl.edu Abstract 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. KATP channel, ATP-sensitive K+ channel PIP2, phosphatidylinositol 4,5-bisphosphate PND, permanent neonatal diabetes SU, sulfonylurea; TND, transient neonatal diabetes Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 26, 2005. Received March 14, 2005. DIABETES