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Lipid roles in hERG function and interactions with drugs

机译:HERG功能和与药物相互作用的脂质作用

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摘要

Human-ether-a-go-go-related channel (hERG) is a voltage gated potassium channel (K(v)11.1) abundantly expressed in heart and brain tissues. In addition to playing an important role in mediation of repolarizing K+ currents (I-kr) in Action Potential (AP), hERG is notorious for its propensity to interact with various medications. The drug-induced block of K+ currents across hERG channel are strongly associated with dysrhythmic conditions collectively known as drug-induced long-QT-syndrome. The recent availability of the high-resolution Cryo-EM structures for the hERG channel has provided unique opportunity to resolve structural mechanisms involved into the process of voltage-gating of hERG channels, map various roles played by components of ventricular and neuronal membranes and then to connect it to cellular pathways through which diverse chemical compounds might be affecting function of the channel. Specifically, lipids and lipid derivatives such as polyunsaturated fatty acids (PUFAs), ceramides and steroids have been shown to directly interact with the lipid facing amino acids in various K-v channels including hERG. In this review, possible lipophilic pathways of hERG activators and blockers, together with the existence of fenestration windows and effects of PUFAs, ceramides and steroids are explored throughout different sections. Finally, the interplay between long QT inducing drugs and phospholipidosis is briefly discussed.
机译:人醚-A-Go-Go-Go-Go-go-go-go-go-go-go-go-go-go-go-go-go-go-go-go-go-goated型钾通道(K(v)11.1)在心脏和脑组织中大量表达。除了在动作潜力(AP)中的复极化K +电流(I-KR)中的调解中发挥重要作用,HERG对于与各种药物相互作用的倾向是臭名昭着的。跨越疱疹通道的药物诱导的K +电流嵌段与统一称为药物诱导的长QT综合征的畸形病症密切相关。最近的HERG频道的高分辨率Cryo-EM结构的可用性提供了独特的机会,可以解决参与HERG通道的电压门过程的结构机制,映射由心室和神经元膜组分发挥的各种角色,然后将其连接到细胞途径,各种化学化合物可能会影响通道的功能。具体而言,已经显示出脂质和脂质衍生物如多不饱和脂肪酸(PUFA),神经酰胺和类固醇,直接与包括HERG的各种K-V通道中面对氨基酸的脂质相互作用。在本次综述中,HERG活化剂和阻滞剂的可能亲脂性途径以及PUFAS窗口的存在以及PUFAS,神经酰胺和类固醇的效果。最后,简要讨论了长QT诱导药物和磷脂的相互作用。

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