上皮细胞K^+通道的生理学意义与临床应用：跨上皮细胞转运的驱动力生成和K^+循环(英文)

Epithelial K^+ channels:driving force generation and K^+ recycling for epithelial transport with physiological and clinical implications

K^+通道在上皮细胞内以极化的方式表达,形成一个庞大的膜蛋白家族。出于对主要依赖Na^+-K^+-ATPase而维持的细胞内跨膜K^+梯度的考虑,K^+通道在跨上皮细胞转运中的主要作用为:膜电位生成和K^+循环。本文以肾近端小管和胃壁上皮细胞转运为例简要阐述了K^+通道的作用。在这两个组织中,K^+通道活性限速跨上皮细胞转运,调节细胞体积。近年来,药理学工具和转基因动物的实验证实了对K^+通道的原先认知,并将研究深入到分子水平。K^+通道的分子结构挑战高亲和力药物分子的设计,及其多组织同时表达的两个典型特征阻碍了高活性、组织特异性小分子治疗的进展。然而,抑制K^+通道能阻断胃酸分泌等病理生理机制的深入研究,促进K^+通道药物用于胃病治疗和作为肾脏转运抑制剂用于肾脏相关疾病治疗。

K^＋ channels form a large family of membrane proteins that are expressed in a polarized fashion in any epithelial cell. Based on the transmembrane gradient for K^＋ that is maintained by the Na^＋-K^＋-ATPase, these channels serve two principal functions for transepithelial transport： generation of membrane voltage and recycling of K^＋. In this brief review, we wiU outline the importance of this ancient principle by examples of epithelial transport in the renal proximal tubule and gastric parietal ceils. In both tissues, K^＋ channel activity is rate-limiting for transport processes across the epithelial ceils and essential for cell volume regulation. Recent experimental data using pharmacological tools and genetically modified animals have confirmed the original physiological concepts and specified the knowledge down to the molecular level. The development of highly active and tissue selective small molecule therapeutics has been impeded by two typical features of K^＋ channels： their molecular architecture challenges the design of molecules with high affinity binding and they are expressed in a variety of tissues at the same time. Nevertheless, new insights into pathophysiology, e.g. that K^＋ channel inhibition can block gastric acid secretion, render the clinical use of K^＋ channel drugs in gastric disease and as kidney transport inhibitors highly attractive.