TY - JOUR
T1 - ATP and sulfonylurea sensitivity of mutant ATP-sensitive K+ channels in neonatal diabetes
T2 - Implications for pharmacogenomic therapy
AU - Koster, Joseph C.
AU - Remedi, Maria S.
AU - Dao, Crystal
AU - Nichols, Colin G.
PY - 2005/9
Y1 - 2005/9
N2 - The prediction that overactivity of the pancreatic ATP-sensitive K + channel (KATP 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 KATP 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 BU drugs as an alternative therapy to insulin injections.
AB - The prediction that overactivity of the pancreatic ATP-sensitive K + channel (KATP 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 KATP 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 BU drugs as an alternative therapy to insulin injections.
UR - http://www.scopus.com/inward/record.url?scp=24144456153&partnerID=8YFLogxK
U2 - 10.2337/diabetes.54.9.2645
DO - 10.2337/diabetes.54.9.2645
M3 - Article
C2 - 16123353
AN - SCOPUS:24144456153
SN - 0012-1797
VL - 54
SP - 2645
EP - 2654
JO - Diabetes
JF - Diabetes
IS - 9
ER -