Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
ChemMedChem. 2012 Oct;7(10):1741-55. doi: 10.1002/cmdc.201200226. Epub 2012 Aug 7.
Ca(2+)-activated K(+) (KCa) channels 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. We discuss the achievements made in designing pharmacological tools that 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 micro-domains in which these channels are expressed within the cell, and finally the retrograde trafficking routes these channels take following endocytosis. As 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 new therapeutic avenues for the targeting of these channels based on the pharmacological modulation of KCa channel density at the plasma membrane.
钙激活钾（KCa）通道在多种组织和疾病状态的生理学中发挥着关键作用，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。这种广泛的参与激发了人们对阐明这些通道的功能和调节的浓厚兴趣，目的是开发针对各种疾病状态下选择性调节 KCa 通道的药理学策略。本文概述了这些通道的分子和功能特性及其治疗重要性。我们讨论了通过调节其门控特性来设计控制 KCa 通道功能的药理学工具所取得的成就。此外，本综述还讨论了我们对 KCa 通道组装和正向运输到质膜的理解的最新进展，这些通道在细胞内表达的微区，以及这些通道在胞吞作用后采取的逆行运输途径。随着激动剂对细胞内运输的调节以及修饰这些事件的蛋白质-蛋白质相互作用的不断探索，我们预计这将为基于药理学调节质膜上 KCa 通道密度来靶向这些通道开辟新的治疗途径。
