Focus on Kir6.2: a key component of the ATP-sensitive potassium channel
Focus on Kir6.2: a key component of the ATP-sensitive potassium channel
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DOI：
10.1016/j.yjmcc.2005.01.007
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发表时间：
2005-06-01
影响因子：
5
通讯作者：
Ashcroft, FM
中科院分区：
文献类型：
--
作者：
Haider, S;Antcliff, JF;Ashcroft, FM
ATP 敏感钾 (K-ATP) 通道存在于多种细胞类型中，它们将细胞代谢与电活动耦合起来。在葡萄糖敏感组织中，这些通道对血糖浓度的波动变化做出反应，但在其他组织中，它们仅在缺血条件下或对激素刺激做出反应时才会被激活。尽管不同组织中的 K-ATP 通道具有不同的调节亚基，但几乎所有情况下（血管平滑肌除外），成孔亚基都是内向整流 K+ 通道 Kit-6.2。本文回顾了 Kit6.2 的最新研究，重点关注通道结构和功能之间的关系，以及导致人类疾病的 Kir6.2 自然发生的突变。结合功能研究讨论了对 ATP 结合位点位置、K+ 渗透途径以及同源模型提供的孔门控的新见解。 Kir6.2 的功能获得突变通过降低 K-ATP 通道的 ATP 敏感性和增加 K-ATP 电流导致永久性新生儿糖尿病 (PNDM)，预计这会抑制 β 细胞电活动和胰岛素分泌。特定残基的突变会导致 ATP 敏感性大幅下降。与其他神经系统症状有关。讨论了这两类突变产生的 ATP 敏感性差异的分子机制。我们推测一些突变如何导致神经系统疾病以及为什么没有观察到明显的心脏症状。我们还考虑了这些研究对 2 型糖尿病的影响。 (c) 2005 Elsevier Ltd. 保留所有权利。
ATP-sensitive potassium (K-ATP)channels are found in a wide variety of cell types where they couple cell metabolism to electrical activity. In glucose-sensing tissues, these channels respond to fluctuating changes in blood glucose concentration, but in other tissues they are activated only under ischemic conditions or in response to hormonal stimulation. Although K-ATP channels in different tissues have different regulatory subunits, in almost all cases (except vascular smooth muscle) the pore-forming subunit is the inwardly rectifying K+ channel Kit-6.2. This article reviews recent studies of Kit6.2, focussing on the relation between channel structure and function, and on naturally occurring mutations in Kir6.2 that lead to human disease. New insights into the location of the ATP-binding site, the permeation pathway for K+, and the gating of the pore provided by homology modelling are discussed in relation to functional studies. Gain-of-function mutations in Kir6.2 cause permanent neonatal diabetes mellitus (PNDM) by reducing the ATP sensitivity of the K-ATP channel and increasing the K-ATP current, which is predicted to inhibit beta-cell electrical activity and insulin secretion. Mutations at specific residues, that cause a greater decrease in ATP sensitivity. are associated with additional neurological symptoms. The molecular mechanism underlying the differences in ATP sensitivity produced by these two classes of mutations is discussed. We speculate on how some mutations lead to neurological disease and why no obvious cardiac symptoms are observed. We also consider the implications of these studies for type-2 diabetes. (c) 2005 Elsevier Ltd. All rights reserved.