Trafficking of intermediate (KCa3.1) and small (KCa2.x) conductance, Ca(2+)-activated K(+) channels: a novel target for medicinal chemistry efforts?
Trafficking of intermediate (KCa3.1) and small (KCa2.x) conductance, Ca(2+)-activated K(+) channels: a novel target for medicinal chemistry efforts?
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DOI：
10.1002/cmdc.201200226
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发表时间：
2012-10
期刊：
影响因子：
3.4
通讯作者：
Devor, Daniel C.
中科院分区：
文献类型：
--
作者：
Balut, Corina M.;Hamilton, Kirk L.;Devor, Daniel C.
Ca2+激活的K+通道（KCa）在多种组织和疾病状态的生理中起着关键作用，包括血管内皮、分泌上皮、某些癌症、红细胞（RBC）、神经元和免疫细胞。这种广泛的参与引起了人们对阐明这些通道的功能和调节的强烈兴趣，目的是开发针对各种疾病状态下KCa通道选择性调节的药理学策略。在此，我们概述了这些通道的分子和功能特性及其治疗重要性，并讨论了在设计通过调节其门控特性来控制KCa通道功能的药理学工具方面取得的成就。此外，本文还讨论了我们对KCa通道组装和向质膜逆行运输的理解的最新进展，这些通道在细胞内表达的微域以及这些通道在内吞作用后所采取的逆行运输路线。随着激动剂对细胞内运输的调节以及改变这些事件的蛋白质-蛋白质相互作用的不断探索，我们预计这将为基于质膜上KCa通道密度的药理学调节的这些通道开辟新的治疗途径。
Ca2+-activated K+ channels (KCa) play a pivotal role in the physiology of a wide variety of tissues and disease states, including vascular endothelia, secretory epithelia, certain cancers, red blood cells (RBC), neurons and immune cells. Such widespread involvement has generated an intense interest in elucidating the function and regulation of these channels, with the goal of developing pharmacological strategies aimed at selective modulation of KCa channels in various disease states. Herein, we give an overview of the molecular and functional properties of these channels and their therapeutic importance as well as discuss the achievements made in designing pharmacological tools which control the function of KCa channels by modulating their gating properties. Moreover, this review discusses the recent advances in our understanding of KCa channel assembly and anterograde trafficking toward the plasma membrane, the microdomains in which these channels are expressed within the cell and finally the retrograde trafficking routes these channels take following endocytosis. As both the regulation of intracellular trafficking by agonists, as well as the protein-protein interactions that modify these events continue to be explored, we anticipate this will open up new therapeutic avenues for the targeting of these channels based on the pharmacological modulation of KCa channel density at the plasma membrane.
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