Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University in Saint Louis, Saint Louis, MO, 63130, USA.
Dalton Cardiovascular Research Center, Department of Physics and Astronomy, Department of Biochemistry, Institute for Data Science & Informatics, University of Missouri, Columbia, MO, 65211, USA.
Commun Biol. 2020 Jul 16;3(1):385. doi: 10.1038/s42003-020-1104-0.
KCNQ family K channels (KCNQ1-5) in the heart, nerve, epithelium and ear require phosphatidylinositol 4,5-bisphosphate (PIP) for voltage dependent activation. While membrane lipids are known to regulate voltage sensor domain (VSD) activation and pore opening in voltage dependent gating, PIP was found to interact with KCNQ1 and mediate VSD-pore coupling. Here, we show that a compound CP1, identified in silico based on the structures of both KCNQ1 and PIP, can substitute for PIP to mediate VSD-pore coupling. Both PIP and CP1 interact with residues amongst a cluster of amino acids critical for VSD-pore coupling. CP1 alters KCNQ channel function due to different interactions with KCNQ compared with PIP. We also found that CP1 returned drug-induced action potential prolongation in ventricular myocytes to normal durations. These results reveal the structural basis of PIP regulation of KCNQ channels and indicate a potential approach for the development of anti-arrhythmic therapy.
KCNQ 家族钾通道（KCNQ1-5）在心脏、神经、上皮和耳朵中需要磷脂酰肌醇 4,5-二磷酸（PIP）才能实现电压依赖性激活。尽管已知膜脂质可调节电压门控通道中的电压传感器域（VSD）激活和孔道开放，但发现 PIP 与 KCNQ1 相互作用并介导 VSD-孔道偶联。在这里，我们展示了一种名为 CP1 的化合物，它是根据 KCNQ1 和 PIP 的结构在计算机上鉴定出来的，可以替代 PIP 来介导 VSD-孔道偶联。PIP 和 CP1 均与 VSD-孔道偶联关键氨基酸簇中的残基相互作用。与 PIP 相比，CP1 通过与 KCNQ 的不同相互作用改变 KCNQ 通道的功能。我们还发现 CP1 使心室肌细胞中药物诱导的动作电位延长恢复到正常持续时间。这些结果揭示了 PIP 调节 KCNQ 通道的结构基础，并表明了开发抗心律失常治疗的潜在方法。
