Mechanisms Underlying the Dual Effect of Polyunsaturated Fatty Acid Analogs on Kv7.1.
Mechanisms Underlying the Dual Effect of Polyunsaturated Fatty Acid Analogs on Kv7.1.
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DOI：
10.1016/j.celrep.2018.08.031
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发表时间：
2018-09-11
期刊：
影响因子：
8.8
通讯作者：
Larsson HP
中科院分区：
文献类型：
--
作者：
Liin SI;Yazdi S;Ramentol R;Barro-Soria R;Larsson HP
多不饱和脂肪酸（PUFA）类似物是潜在的抗肿瘤化合物，了解其功能机制有助于合理的药物设计。Liin等人发现，带负电荷的PUFA类似物通过双重独立机制激活心脏钾通道KV7.1，表明通过与KV7.1的孔和电压敏感结构域的静电相互作用增强通道活性。多不饱和脂肪酸（PUFA）类似物代表了一类新的潜在的抗肿瘤KV 7.1和KV 7.1 +KCNE1通道激活剂。在这项研究中，我们描述了双独立的激活作用的负电荷PUFA类似物上的KV 7.1和KV 7.1 +KCNE1是依赖于离散的通道图案。PUFA类似物临界依赖于KV7.1的S6中的K326以增加最大电导，并且临界依赖于KV7.1中的特定S4丝氨酸以将通道开放的电压依赖性向负电压偏移。我们的研究结果提供了KV7.1+KCNE1激活剂如何与孔结构域和电压敏感结构域静电相互作用以增强通道活性的见解。我们相信，从分子水平上理解PUFA类似物如何诱导双重独立激活作用是开发靶向KV7.1通道的有效抗血小板药物的重要一步。
Polyunsaturated fatty acid (PUFA) analogs are potentially anti-arrhythmic compounds, and understanding their functional mechanisms can aid in rational drug design. Liin et al. find that negatively charged PUFA analogs activate the cardiac potassium channel KV7.1 by dual independent mechanisms, demonstrating augmentation of channel activity through electrostatic interactions with both the pore and voltage-sensing domains of KV7.1. Polyunsaturated fatty acid (PUFA) analogs represent a new class of potential anti-arrhythmic KV7.1 and KV7.1+KCNE1 channel activators. In this study, we describe dual independent activating effects of negatively charged PUFA analogs on KV7.1 and KV7.1+KCNE1 that are dependent on discrete channel motifs. PUFA analogs are critically dependent on K326 in S6 of KV7.1 to increase the maximum conductance and critically dependent on specific S4 arginines in KV7.1 to shift the voltage dependence of channel opening toward negative voltages. Our findings provide insights into how KV7.1+KCNE1 activators may interact electrostatically both with the pore domain and the voltage-sensing domain to augment channel activity. We believe that the molecular understanding of how PUFA analogs induce dual independent activating effects is an important step toward the development of effective anti-arrhythmic drugs that target KV7.1 channels.
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