From Selective Permeation to Physiology in Potassium Channels

Highly K⁺-selective potassium channels are essential for electrical signaling. The high selectivity of most K⁺ channels, with relative K⁺: Na⁺ permeabilities being as high as 100–1000:1 arises from the conserved so-called K⁺ channel selectivity filter (SF). Structural and computational studies have shown how the SF forms multiple sites that coordinate K⁺, by mimicking the water dipoles that coordinate K⁺ ions in solution, and thermodynamically favoring the binding of K⁺ over Na⁺. Selective conduction of K⁺ ions then results from a “knock-on” mechanism, whereby entering ions destabilize the next ion in the file. This review highlights key biophysical and biochemical research that provides insights to the atomic details of these processes. It then discusses how mutations that alter K⁺ selectivity and permeation in different K⁺ channels underlie multiple simple and complex diseases, illustrating how selectivity and permeation are central to physiology and to pathophysiology and important for physiologists to be aware of.