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

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 will outline the importance of this ancient principle by examples of epithelial transport in the renal proximal tubule and gastric parietal cells. In both tissues, K(+) channel activity is rate-limiting for transport processes across the epithelial cells 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.