Abstract
Inactivation, the slow cessation of transmission after activation, is a general feature of potassium channels. It is essential for their function, and malfunctions in inactivation leads to numerous pathologies. The detailed mechanism for the C-type inactivation, distinct from the N-type inactivation, remains an active area of investigation. Crystallography, computational simulations, and NMR have greatly enriched our understanding of the process. Here we review the major hypotheses regarding C-type inactivation, particularly focusing on the key role played by NMR studies of the prokaryotic potassium channel KcsA, which serves as a good model for voltage gated mammalian channels.
Highlights
Potassium channels form the second largest family of membrane proteins, and control numerous metabolic processes
A recent study by Heer et al argues that the selectivity filter might play a critical role in the activation: through molecular dynamic simulation and electrophysiological study on a mutant, they implied that opening the pH gate can relax the selectivity filter and cause a loose affinity towards K+, which leads to ion conducting; they reasoned that the high K+ affinity at the selectivity filter could lead to a high activation energy for ion hopping (Heer et al, 2017)
It is hypothesized that the bulky sidechain in F103 interacts with I100 and T74 to mediate the coupling from activation gate to the selectivity filter. We explored this hypothesis and find that protonation at the pH gate for an F103A mutant has a much weaker effect on potassium affinity at the selectivity filter than in the WT-KcsA (2uM to 300uM for F103A comparing to 4uM to 14 mM for WT-KcsA), suggesting that the coupling strength was perturbed by the mutant (Fig. 4c–h)
Summary
Potassium channels form the second largest family of membrane proteins, and control numerous metabolic processes. In a wide array of organisms, including plants, bacteria, and even some viruses they play crucial roles in maintaining the cell potential which forms an energy reservoir and can be coupled to numerous other processes (Jentsch, 2000; Prindle et al, 2015) In excitable cells, such as neurons and muscles they control electrical conduction, taking advantage of the large concentration differences for sodium and potassium ions. In the C-terminus, transmembrane helices are bundled together to prevent hydrated ions (∼8 Å) from entering the channels, forming the activation gate (Bezanilla et al, 1991; Liu et al, 2001; Shimizu et al, 2008) These residues are sensitive to voltage or ligand binding; when activated they induce movement of helices to open the channel (Jensen et al, 2012; Sand et al, 2013). A recent study by Heer et al argues that the selectivity filter might play a critical role in the activation: through molecular dynamic simulation and electrophysiological study on a mutant, they implied that opening the pH gate can relax the selectivity filter and cause a loose affinity towards K+, which leads to ion conducting; they reasoned that the high K+ affinity at the selectivity filter could lead to a high activation energy for ion hopping (Heer et al, 2017)
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