Panyi G, Possani L D, Rodríguez de la Vega R C, Gáspár R, Varga Z
Department of Biophysics and Cell Biology, University of Debrecen, Medical and Health Science Center, 98. Nagyerdei krt., Debrecen 4012 Hungary.
Curr Pharm Des. 2006;12(18):2199-220. doi: 10.2174/138161206777585120.
During the last two decades since the identification and characterization of T cell potassium channels great advances have been made in the understanding of the role of these channels in T cell functions, especially in antigen-induced activation. Their limited tissue distribution and the recent discovery that different T cell subtypes carrying out distinct immune functions show specific expression levels of these channels have made T cell potassium channels attractive targets for immunomodulatory drugs. Many toxins of various animal species and a structurally diverse array of small molecules inhibiting these channels with varying affinity and selectivity were found and their successful use in immunosuppression in vivo was also demonstrated. Better understanding of the topological differences between potassium channel pores, detailed knowledge of toxin and small-molecule structures and the identification of the binding sites of blocking compounds make it possible to improve the selectivity and affinity of the lead compounds by introducing modifications based on structural information. In this review the basic properties and physiological roles of the voltage-gated Kv1.3 and the Ca2+-activated IKCa1 potassium channels are discussed along with an overview of compounds inhibiting these channels and approaches aiming at producing more efficient modulators of immune functions for the treatment of diseases like sclerosis multiplex and type I diabetes.
自从T细胞钾通道被鉴定和表征以来的过去二十年里，在理解这些通道在T细胞功能中的作用，尤其是在抗原诱导的激活过程中的作用方面取得了巨大进展。它们有限的组织分布以及最近的发现，即执行不同免疫功能的不同T细胞亚型显示出这些通道的特定表达水平，使得T细胞钾通道成为免疫调节药物有吸引力的靶点。人们发现了各种动物物种的许多毒素以及一系列结构多样的小分子，它们以不同的亲和力和选择性抑制这些通道，并且还证明了它们在体内免疫抑制中的成功应用。对钾通道孔之间拓扑差异的更好理解、对毒素和小分子结构的详细了解以及对阻断化合物结合位点的鉴定，使得基于结构信息进行修饰来提高先导化合物的选择性和亲和力成为可能。在这篇综述中，讨论了电压门控Kv1.3和Ca2+激活的IKCa1钾通道的基本特性和生理作用，同时概述了抑制这些通道的化合物以及旨在生产更有效的免疫功能调节剂以治疗多发性硬化症和I型糖尿病等疾病的方法。
