K(V) Channel-Interacting Proteins in the Neurological and Cardiovascular Systems: An Updated Review.
K(V) Channel-Interacting Proteins in the Neurological and Cardiovascular Systems: An Updated Review.
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DOI：
10.3390/cells12141894
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发表时间：
2023-07-20
期刊：
影响因子：
6
通讯作者：
Liu, Jie
中科院分区：
文献类型：
--
作者：
Wu, Le-Yi;Song, Yu-Juan;Zhang, Cheng-Lin;Liu, Jie
KV通道相互作用蛋白（KChIP 1 -4）属于Ca 2+结合EF手蛋白家族，能够与KV 4通道α亚基的N端结合。KChIP主要在大脑和心脏中表达，在那里它们通过调节快速失活-KV 4电流来维持神经元和心肌细胞的兴奋性。KChIPs作为辅助亚基，在调节KV 4通道的表面蛋白表达和门控特性中发挥重要作用。从机制上讲，KChIP 1、KChIP 2和KChIP 3促进KV 4通道易位至细胞膜，加速电压依赖性激活，并减慢失活的恢复速率，从而增加KV 4电流。相比之下，KChIP 4抑制KV 4运输并消除KV 4电流的快速失活。在心脏中，IKs、伊卡、L和INa也可以由KChIPs调节。KChIP 2对伊卡、L和INa有正调节作用，而对IKs有负调节作用。有趣的是，KChIP 3也被称为下游调节元件拮抗剂调节剂（DREAM），因为它可以直接结合到靶基因启动子上的下游调节元件（DRE），这些靶基因涉及疼痛，记忆，内分泌，免疫和炎症反应的调节。此外，所有的KChIPs都可以作为转录因子抑制参与昼夜节律调节的基因的表达。KChIPs的表达改变与几种神经和心血管疾病的发病机制有关。例如，KChIP 2在衰竭的心脏中减少，而KChIP 2的缺失导致对心律失常的易感性增加。KChIP 3在阿尔茨海默病和肌萎缩侧索硬化中增加，但在癫痫和亨廷顿病中减少。本文就KChIPs的结构特征、生理功能以及在健康和疾病中的病理作用等方面的最新研究进展进行综述。我们还总结了调节KChIPs功能的小分子化合物。本文将对KChIP家族的调控机制和靶向药物的研究进展进行综述和更新，以供相关领域研究者参考。
KV channel-interacting proteins (KChIP1-4) belong to a family of Ca2+-binding EF-hand proteins that are able to bind to the N-terminus of the KV4 channel α-subunits. KChIPs are predominantly expressed in the brain and heart, where they contribute to the maintenance of the excitability of neurons and cardiomyocytes by modulating the fast inactivating-KV4 currents. As the auxiliary subunit, KChIPs are critically involved in regulating the surface protein expression and gating properties of KV4 channels. Mechanistically, KChIP1, KChIP2, and KChIP3 promote the translocation of KV4 channels to the cell membrane, accelerate voltage-dependent activation, and slow the recovery rate of inactivation, which increases KV4 currents. By contrast, KChIP4 suppresses KV4 trafficking and eliminates the fast inactivation of KV4 currents. In the heart, IKs, ICa,L, and INa can also be regulated by KChIPs. ICa,L and INa are positively regulated by KChIP2, whereas IKs is negatively regulated by KChIP2. Interestingly, KChIP3 is also known as downstream regulatory element antagonist modulator (DREAM) because it can bind directly to the downstream regulatory element (DRE) on the promoters of target genes that are implicated in the regulation of pain, memory, endocrine, immune, and inflammatory reactions. In addition, all the KChIPs can act as transcription factors to repress the expression of genes involved in circadian regulation. Altered expression of KChIPs has been implicated in the pathogenesis of several neurological and cardiovascular diseases. For example, KChIP2 is decreased in failing hearts, while loss of KChIP2 leads to increased susceptibility to arrhythmias. KChIP3 is increased in Alzheimer’s disease and amyotrophic lateral sclerosis, but decreased in epilepsy and Huntington’s disease. In the present review, we summarize the progress of recent studies regarding the structural properties, physiological functions, and pathological roles of KChIPs in both health and disease. We also summarize the small-molecule compounds that regulate the function of KChIPs. This review will provide an overview and update of the regulatory mechanism of the KChIP family and the progress of targeted drug research as a reference for researchers in related fields.
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影响因子：
5.5
作者：
Beckett, Elizabeth A. H.;McCloskey, Conor;Koh, Sang Don
通讯作者：
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DOI：
10.1152/ajpheart.00587.2016
发表时间：
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影响因子：
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