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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.
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Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.

机译：与新生儿糖尿病或新生儿糖尿病相关的Kir6.2突变的分子基础加上神经系统特征。

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摘要

Inwardly rectifying potassium channels (Kir channels) control cell membrane K(+) fluxes and electrical signaling in diverse cell types. Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive (K(ATP)) channel, cause permanent neonatal diabetes mellitus (PNDM). For some mutations, PNDM is accompanied by marked developmental delay, muscle weakness, and epilepsy (severe disease). To determine the molecular basis of these different phenotypes, we expressed wild-type or mutant (R201C, Q52R, or V59G) Kir6.2/sulfonylurea receptor 1 channels in Xenopus oocytes. All mutations increased resting whole-cell K(ATP) currents by reducing channel inhibition by ATP, but, in the simulated heterozygous state, mutations causing PNDM alone (R201C) produced smaller K(ATP) currents and less change in ATP sensitivity than mutations associated with severe disease (Q52R and V59G). This finding suggests that increased K(ATP) currents hyperpolarize pancreatic beta cells and impair insulin secretion, whereas larger K(ATP) currents are required to influence extrapancreatic cell function. We found that mutations causing PNDM alone impair ATP sensitivity directly (at the binding site), whereas those associated with severe disease act indirectly by biasing the channel conformation toward the open state. The effect of the mutation on ATP sensitivity in the heterozygous state reflects the different contributions of a single subunit in the Kir6.2 tetramer to ATP inhibition and to the energy of the open state. Our results also show that mutations in the slide helix of Kir6.2 (V59G) influence the channel kinetics, providing evidence that this domain is involved in Kir channel gating, and suggest that the efficacy of sulfonylurea therapy in PNDM may vary with genotype.
机译：向内整流钾通道（Kir通道）控制细胞膜K（+）通量和不同细胞类型中的电信号传导。人Kir6.2基因（KCNJ11）的杂合突变是ATP敏感（K（ATP））通道的成孔亚基，会导致永久性新生儿糖尿病（PNDM）。对于某些突变，PNDM伴随着明显的发育延迟，肌肉无力和癫痫病（严重疾病）。为了确定这些不同表型的分子基础，我们在非洲爪蟾卵母细胞中表达了野生型或突变型（R201C，Q52R或V59G）Kir6.2 /磺酰脲受体1通道。所有突变均通过减少ATP的通道抑制作用而增加了静息全细胞K（ATP）电流，但是在模拟的杂合状态下，仅导致PNDM（R201C）的突变产生的K（ATP）电流较小，并且与相关突变相比，ATP敏感性的变化较小患有严重疾病（Q52R和V59G）。这一发现表明，增加的K（ATP）电流会使胰岛β细胞超极化并损害胰岛素分泌，而需要更大的K（ATP）电流来影响胰腺外细胞的功能。我们发现，单独导致PNDM的突变会直接（在结合位点）削弱ATP敏感性，而与严重疾病相关的突变则通过将通道构型偏向开放状态而间接起作用。杂合状态下突变对ATP敏感性的影响反映了Kir6.2四聚体中单个亚基对ATP抑制和开放态能量的不同贡献。我们的结果还表明，Kir6.2（V59G）玻片螺旋中的突变影响通道动力学，提供了该域与Kir通道门控有关的证据，并表明磺酰脲治疗PNDM的功效可能因基因型而异。

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