Photochromic blockers of voltage-gated potassium channels.
Photochromic blockers of voltage-gated potassium channels.
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DOI：
10.1002/anie.200904504
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发表时间：
2009
影响因子：
16.6
通讯作者：
Trauner, Dirk
中科院分区：
文献类型：
--
作者：
Banghart, Matthew R.;Mourot, Alexandre;Fortin, Doris L.;Yao, Jennifer Z.;Kramer, Richard H.;Trauner, Dirk
光致变色配体（PCLs）可以在显示不同生物活性的异构体之间进行光学转换。因此，它们提供了将配体驱动的途径转化为光驱动的途径的机会，从而使用光控制广泛的生物过程成为可能。已针对各种类型的靶蛋白探索了PCL，包括酶、[1-3]配体门控离子通道[4-6]和G蛋白偶联受体。[7]例如，烟碱乙酰胆碱受体（一种配体门控离子通道）的光致变色激动剂[5]和拮抗剂[8]在30多年前就有描述。最近，我们已经引入了一种光致变色形式的谷氨酸盐，它在红藻氨酸盐受体上充当PCL，并可用于触发神经元放电。[6]PCL方法在神经系统中可能特别有效，其中细胞兴奋性的非线性性质可能会加剧异构体之间功效或不完全光转化的相对较小的变化。我们在此报告了一个靶向四聚体电压门控离子通道的两亲性偶氮苯分子家族（图1a）。这种类型的通道不被细胞外配体门控，但可以被小分子如亲脂性阳离子阻断。[9，10]我们的分子作为电压门控K+通道的光致变色阻断剂，作用于细胞内四乙基铵（TEA）结合位点（图1b）。它们可以从细胞外侧应用，并且在单次短暂应用后在细胞中具有持久的效果。在可兴奋的细胞中，它们作为光致变色神经调节剂，可用于光学控制动作电位firing.We以前报道的分子AAQ（丙烯酰胺-偶氮-季铵，1），这是光敏化野生型K+通道。[11]我们假设AAQ在外部四乙基铵（TEA）结合位点处作为光开关栓系配体（PTL）发挥作用，并且它将通过亲和标记附着于天然残基（图1c）。然而，我们试图验证该研究中心的相互作用，但没有得出结论（支持性信息中的图S1和S2）。相反，我们的机理研究表明AAQ不是共价结合的，而是在内部TEA结合位点充当PCL（图1b）。钾通道不仅被烷基铵离子阻断在外部的四乙基铵（TEA）
Photochromic ligands (PCLs) can be optically switched between isomers that show different biological activities. As such, they offer an opportunity to convert ligand-actuated pathways into light-actuated pathways, thus making it possible to control a wide range of biological processes with light. PCLs have been explored for various classes of target proteins, including enzymes,[1–3] ligand-gated ion channels,[4–6] and G-protein-coupled receptors.[7] For instance, photochromic agonists [5] and antagonists [8] for the nicotinic acetylcholine receptor, a ligand-gated ion channel, were described more than thirty years ago. More recently, we have introduced a photochromic version of glutamate that acts as a PCL on kainate receptors and can be used to trigger neuronal firing.[6] The PCL approach can be particularly effective in neural systems, where the nonlinear nature of cellular excitability can accentuate relatively small changes in efficacy or incomplete photoconversion between isomers. We report herein a family of amphiphilic azobenzene molecules that target tetrameric voltage-gated ion channels (Figure 1a). Channels of this type are not gated by extracellular ligands but can be blocked by small molecules such as lipophilic cations.[9, 10] Our molecules function as photochromic blockers of voltage-gated K+ channels and act on the intracellular tetraethylammonium (TEA) binding site (Figure 1b). They can be applied from the extracellular side and have long-lasting effects in cells after a single, transient application. In excitable cells, they function as photochromic neuromodulators and can be used to optically control action potential firing.We have previously reported the molecule AAQ (Acrylamide-Azo-Quaternary ammonium, 1), which was shown to photosensitize wild-type K+ channels.[11] We had hypothesized that AAQ functions as a photoswitchable tethered ligand (PTL) at the external tetraethylammonium (TEA) binding site and that it would attach to native residues through affinity labeling (Figure1c). However, our attempts to verify an interaction at this site were inconclusive (Figures S1 and S2 in the Supporting Information). Instead, our mechanistic studies indicate that AAQ is not covalently bound and acts as a PCL at the internal TEA binding site (Figure 1b). Potassium channels are not only blocked by alkyl ammonium ions at the external tetraethylammonium (TEA)
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DOI：
10.1085/jgp.58.4.413
发表时间：
1971-10
期刊：
The Journal of general physiology
影响因子：
--
作者：
Armstrong CM
通讯作者：
Armstrong CM
影响因子：
3.4
作者：
FRENCH, RJ;SHOUKIMAS, JJ
通讯作者：
SHOUKIMAS, JJ
影响因子：
56.9
作者：
MACKINNON, R;YELLEN, G
通讯作者：
YELLEN, G
影响因子：
3.8
作者：
ARMSTRONG, CM
通讯作者：
ARMSTRONG, CM
DOI：
10.1073/pnas.68.8.1820
发表时间：
1971-01-01
影响因子：
11.1
作者：
BARTELS, E;WASSERMANN, NH;ERLANGER, BF
通讯作者：
ERLANGER, BF