Girard Christophe A J, Shimomura Kenju, Proks Peter, Absalom Nathan, Castano Luis, Perez de Nanclares Guiomar, Ashcroft Frances M
University Laboratory of Physiology, Oxford University, Oxford, OX1 3PT, UK.
Pflugers Arch. 2006 Dec;453(3):323-32. doi: 10.1007/s00424-006-0112-3. Epub 2006 Sep 22.
ATP-sensitive potassium (K(ATP)) channels, composed of pore-forming Kir6.2 and regulatory sulphonylurea receptor (SUR) subunits, play an essential role in insulin secretion from pancreatic beta cells. Binding of ATP to Kir6.2 inhibits, whereas interaction of Mg-nucleotides with SUR, activates the channel. Heterozygous activating mutations in Kir6.2 (KCNJ11) are a common cause of neonatal diabetes (ND). We assessed the functional effects of six novel Kir6.2 mutations associated with ND: H46Y, N48D, E227K, E229K, E292G, and V252A. K(ATP) channels were expressed in Xenopus oocytes and the heterozygous state was simulated by coexpression of wild-type and mutant Kir6.2 with SUR1 (the beta cell type of SUR). All mutations reduced the sensitivity of the K(ATP) channel to inhibition by MgATP, and enhanced whole-cell K(ATP) currents. Two mutations (E227K, E229K) also enhanced the intrinsic open probability of the channel, thereby indirectly reducing the channel ATP sensitivity. The other four mutations lie close to the predicted ATP-binding site and thus may affect ATP binding. In pancreatic beta cells, an increase in the K(ATP) current is expected to reduce insulin secretion and thereby cause diabetes. None of the mutations substantially affected the sensitivity of the channel to inhibition by the sulphonylurea tolbutamide, suggesting patients carrying these mutations may respond to these drugs.
由成孔亚基Kir6.2和调节性磺脲类受体（SUR）亚基组成的ATP敏感性钾通道（K(ATP)通道）在胰腺β细胞分泌胰岛素过程中发挥着重要作用。ATP与Kir6.2结合会抑制该通道，而镁核苷酸与SUR相互作用则会激活该通道。Kir6.2（KCNJ11）中的杂合激活突变是新生儿糖尿病（ND）的常见病因。我们评估了与ND相关的6种新型Kir6.2突变的功能效应：H46Y、N48D、E227K、E229K、E292G和V252A。K(ATP)通道在非洲爪蟾卵母细胞中表达，通过野生型和突变型Kir6.2与SUR1（SUR的β细胞类型）共表达来模拟杂合状态。所有突变均降低了K(ATP)通道对MgATP抑制的敏感性，并增强了全细胞K(ATP)电流。两个突变（E227K、E229K）还增强了通道的内在开放概率，从而间接降低了通道对ATP的敏感性。其他四个突变位于预测的ATP结合位点附近，因此可能影响ATP结合。在胰腺β细胞中，预计K(ATP)电流增加会减少胰岛素分泌，从而导致糖尿病。这些突变均未实质性影响通道对磺脲类药物甲苯磺丁脲抑制的敏感性，这表明携带这些突变的患者可能对这些药物有反应。
