Pore- and voltage sensor-targeted KCNQ openers have distinct state-dependent actions.
Pore- and voltage sensor-targeted KCNQ openers have distinct state-dependent actions.
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DOI：
10.1085/jgp.201812070
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发表时间：
2018-12-03
期刊：
影响因子：
--
通讯作者：
Kurata HT
中科院分区：
文献类型：
--
作者：
Wang CK;Lamothe SM;Wang AW;Yang RY;Kurata HT
KCNQ 2 -5电压门控钾通道被许多不同的化合物激活，这些化合物将激活的电压依赖性转移到更负的电压。Wang等人表明，孔和电压传感器靶向活化剂具有不同的状态依赖性作用，因此具有不同的机制。由KCNQ 2 -5编码的离子通道在中枢神经系统中产生显著的K+电导，称为M电流，其由膜电压和PIP 2控制。KCNQ 2 -5电压门控钾通道被多种激活化合物靶向，这些化合物导致激活的电压依赖性负移。由于可能的临床应用，这些作用的潜在药理学越来越受到关注。最近的研究揭示了KCNQ激活剂的多个结合位点和作用机制。例如，瑞替加宾靶向孔结构域，但有几种化合物已被证明会影响电压敏感结构域。这些化合物的一个重要的未探索的特征是通道门控对药物结合或作用的影响。在本研究中，我们比较了瑞替加滨和伊卡-069673（ICA 73，一种电压传感器靶向激活剂）的状态依赖性作用。我们通过在不同的保持电压下将药物应用于同聚体KCNQ 2通道来评估药物与预开放状态的结合，证明ICA 73与静息状态很少或没有关联。使用快速的解决方案切换，我们还表明，ICA 73的发病率与通道激活的电压依赖性。瑞替加滨的作用显著不同，在非常负的保持电压下观察到显著的药物作用，并且药物结合与通道激活具有明显的电压依赖性。使用类似的方法，我们研究了电压敏感结构域突变KCNQ 2 [A181 P]减弱ICA 73作用的机制基础。我们的研究结果证明了孔与电压传感器靶向KCNQ通道激活剂的不同状态依赖性作用，这突出了这类药物的亚型以不同的机制运作。
The KCNQ2-5 voltage-gated potassium channels are activated by a number of different compounds that shift the voltage dependence of activation to more negative voltages. Wang et al. show that pore- and voltage sensor–targeted activators have different state-dependent actions and therefore distinct mechanisms. Ion channels encoded by KCNQ2-5 generate a prominent K+ conductance in the central nervous system, referred to as the M current, which is controlled by membrane voltage and PIP2. The KCNQ2-5 voltage-gated potassium channels are targeted by a variety of activating compounds that cause negative shifts in the voltage dependence of activation. The underlying pharmacology of these effects is of growing interest because of possible clinical applications. Recent studies have revealed multiple binding sites and mechanisms of action of KCNQ activators. For example, retigabine targets the pore domain, but several compounds have been shown to influence the voltage-sensing domain. An important unexplored feature of these compounds is the influence of channel gating on drug binding or effects. In the present study, we compare the state-dependent actions of retigabine and ICA-069673 (ICA73, a voltage sensor–targeted activator). We assess drug binding to preopen states by applying drugs to homomeric KCNQ2 channels at different holding voltages, demonstrating little or no association of ICA73 with resting states. Using rapid solution switching, we also demonstrate that the rate of onset of ICA73 correlates with the voltage dependence of channel activation. Retigabine actions differ significantly, with prominent drug effects seen at very negative holding voltages and distinct voltage dependences of drug binding versus channel activation. Using similar approaches, we investigate the mechanistic basis for attenuation of ICA73 actions by the voltage-sensing domain mutation KCNQ2[A181P]. Our findings demonstrate different state-dependent actions of pore- versus voltage sensor–targeted KCNQ channel activators, which highlight that subtypes of this drug class operate with distinct mechanisms.
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影响因子：
30.8
作者：
Charlier, C;Singh, NA;Leppert, M
通讯作者：
Leppert, M
影响因子：
11.4
作者：
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通讯作者：
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DOI：
10.1073/pnas.0911294107
发表时间：
2010-08-31
影响因子：
11.1
作者：
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通讯作者：
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DOI：
10.1073/pnas.1705802114
发表时间：
2017-11-07
影响因子：
11.1
作者：
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通讯作者：
Kurata HT
影响因子：
16.6
作者：
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