Mechanistic insights into robust cardiac I Ks potassium channel activation by aromatic polyunsaturated fatty acid analogues.
Mechanistic insights into robust cardiac I Ks potassium channel activation by aromatic polyunsaturated fatty acid analogues.
复制标题
芳香族多不饱和脂肪酸类似物强效心脏 IKs 钾通道激活的机制见解。
DOI：
10.1101/2023.01.12.523777
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Larsson,HPeter
中科院分区：
文献类型：
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作者：
Bohannon,BrianaM;Jowais,JessicaJ;Nyberg,Leif;Liin,SaraI;Larsson,HPeter
电压门控钾 (K V) 通道是细胞兴奋性的重要调节器，并控制心脏和大脑的动作电位复极化。 K V 通道突变导致细胞兴奋性紊乱。例如，功能丧失突变会导致膜过度兴奋，这是癫痫和心律失常的一个特征。旨在恢复 KV 通道功能的干预措施在此类疾病中具有强大的治疗潜力。多不饱和脂肪酸 (PUFA) 和 PUFA 类似物包含一类 K V 通道激活剂，在治疗长 QT 综合征 (LQTS) 等心律失常疾病方面具有潜在应用。 LQTS 是由心脏 I Ks 通道功能丧失引起的，I Ks 通道是由 K V 7.1 和相关 KCNE1 蛋白亚基形成的四聚体钾通道复合物。我们发现了一组芳香族 PUFA 类似物，可以强烈激活心脏 I Ks 通道，这些 PUFA 类似物的独特特征是芳香族酪氨酸头基。我们确定了酪氨酸 PUFA 类似物通过生成修饰的芳香族头基对 I Ks 通道发挥强激活作用的机制，该芳香族头基旨在探测阳离子-π 相互作用、氢键和离子相互作用。我们发现酪氨酸 PUFA 类似物不会通过阳离子-π 相互作用激活 I Ks 通道，而是通过氢键和离子相互作用的组合来激活 I Ks 通道。
Voltage-gated potassium (K V) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. K V channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a characteristic of epilepsy and cardiac arrhythmias. Interventions intended to restore K V channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of K V channel activators with potential applications in the treatment of arrhythmogenic disorders such as long QT syndrome (LQTS). LQTS is caused by a loss-of-function of the cardiac I Ks channel–a tetrameric potassium channel complex formed by K V 7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac I Ks channel, and a unique feature of these PUFA analogues is an aromatic, tyrosine head group. We determine the mechanisms through which tyrosine PUFA analogues exert strong activating effects on the I Ks channel by generating modified aromatic head groups designed to probe cation–pi interactions, hydrogen bonding, and ionic interactions. We found that tyrosine PUFA analogues do not activate the I Ks channel through cation–pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.