Gating mechanism of KATP channels: function fits form.
Gating mechanism of KATP channels: function fits form.
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DOI：
10.1085/jgp.200308878
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发表时间：
2003-11
期刊：
影响因子：
--
通讯作者：
Nichols CG
中科院分区：
文献类型：
--
作者：
Enkvetchakul D;Nichols CG
最初基于它们在鱿鱼巨轴突中的突出性、它们有用的药理学以及随后作为第一个克隆的K通道，电压门控K（Kv）通道已经因其生物物理特性而受到最大的关注。Kv和Ca激活的K通道动力学和门控机制已被详细分析和建模（Hille，2001）。内向整流钾离子通道受到较少的关注，阅读文献表明，仍然没有共同的理解动力学机制的Kir通道。然而，我们的论点是，一个目标是可以实现的。在Kir通道中，ATP敏感性（KATP）通道由细胞质核苷酸和特定药理学试剂独特地调节。因此，它们在将细胞代谢与电活动偶联中起关键作用，并且是胰腺、血管平滑肌和心肌中的主要药物靶标（Ashcroft，1988; Nichols和Lederer，1991）。我们认为，这些独特的属性也允许阐明通道门控的重要功能，是相关的整个类的基尔渠道。在过去的二十年里，KATP通道调节的分子机制占据了许多小组。动力学测量已经导致门控的数学模型，诱变已经指示相关的分子元件，并且各种K通道亚基和结构域的结晶现在为通道结构提供模板。从这些数据中提炼出一个一致的通道活动和调节模型是该领域的挑战，也是本次简要回顾的主题。KATP通道由四个Kir 6组成。2个孔形成亚基和4个调节磺酰脲受体（SUR）亚基（Clement等，1997; Inagaki等人，1997; Shyng和Nichols，1997）（图1）。活性受到电压和多种配体（包括作用于Kir 6的ATP和PIP 2）的调节。2亚基本身，以及磺酰脲类，钾通道开放剂和Mg-核苷酸，其作用于SUR亚基。抑制性ATP与Kir 6结合。2亚基，而MgATP-和ADP-活化由与SUR亚基的相互作用引起（Matsuo et al.，1999，2000;田边等人，1999;上田等人，1999; MacGregor等人，2002; Vanoye等人，2002年）。KATP通道行为无疑是复杂的，目前还不可能建立一个完整的通道活性动力学模型，包括通过SUR亚基进行药理学调节。然而，我们将争辩说，Kir 6的一致模型。2通道活性确实会出现，并且从这个模型中，异聚复合物的额外复杂性最终会出现。我们将首先考虑如何热力学和动力学测量导致一个模型，可以解释门控，然后考虑这种行为的结构基础。
Based initially on their prominence in the squid giant axon, their useful pharmacology, and subsequently on being the first cloned K channels, voltage-gated K (Kv) channels have received the lion’s share of attention to their biophysical properties. Kv and Ca-activated K channel kinetics and gating mechanisms have been analyzed, and modeled, in exquisite detail (Hille, 2001). Inward rectifier K (Kir) channels have received less attention, and perusal of the literature indicates that there is still no common understanding of kinetic mechanisms in Kir channels. It is our contention, however, that one is in reach. Amongst Kir channels, ATP-sensitive (KATP) channels are uniquely regulated by cytoplasmic nucleotides and specific pharmacological agents. As such, they play a critical role in coupling cellular metabolism to electrical activity, and are major drug targets in pancreatic, vascular smooth muscle and cardiac muscle (Ashcroft, 1988; Nichols and Lederer, 1991). We would argue that these unique properties also permit elucidation of important features of channel gating that are relevant to the whole class of Kir channels. The molecular mechanisms of KATP channel regulation have occupied many groups for the last twenty years. Kinetic measurements have led to mathematical models of gating, mutagenesis has indicated relevant molecular elements, and crystallization of various K channel subunits and domains now provides templates for the channel structure. Distilling a consistent model of channel activity and regulation from this broth of data is the challenge for the field, and the topic of this Brief Review. The KATP channel is formed from four Kir6. 2 pore–forming subunits, and four regulatory sulfonylurea receptor (SUR) subunits (Clement et al., 1997; Inagaki et al., 1997; Shyng and Nichols, 1997)(Fig. 1). Activity is modulated by voltage and by multiple ligands, including ATP and PIP2, which act on the Kir6. 2 subunits themselves, as well as sulfonylureas, potassium channel openers, and Mg-nucleotides, which act on the SUR subunit. Inhibitory ATP binds to the Kir6. 2 subunit, while MgATP-and ADP-activation results from interaction with the SUR subunits (Matsuo et al., 1999, 2000; Tanabe et al., 1999; Ueda et al., 1999; MacGregor et al., 2002; Vanoye et al., 2002). KATP channel behavior is undoubtedly complex, and at present a complete kinetic model of channel activity, including pharmacological regulation through the SUR subunits is impossible. However, we will argue that a consistent model of Kir6. 2 channel activity does arise, and that from this model, the additional complexity of heteromeric complexes will ultimately emerge. We will first consider how thermodynamic and kinetic measurements lead to a model that can explain gating, then consider the structural basis of this behavior.
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影响因子：
56.9
作者：
Doyle, DA;Cabral, JM;MacKinnon, R
通讯作者：
MacKinnon, R
影响因子：
3.8
作者：
Holmgren, M;Smith, PL;Yellen, G
通讯作者：
Yellen, G
DOI：
10.1085/jgp.118.2.157
发表时间：
2001-08
期刊：
The Journal of general physiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.4
作者：
Enkvetchakul, D;Loussouarn, G;Nichols, CG
通讯作者：
Nichols, CG
影响因子：
56.9
作者：
Baukrowitz, T;Schulte, U;Fakler, B
通讯作者：
Fakler, B