The strange phenomenon of random activity jumps in ion channels

Researchers from Utrecht University and the University of Chicago have unravelled the molecular basis of a widespread yet poorly understood regulatory mechanism called ‘modal gating’ in ion channels. Modal gating means that ion channels seemingly randomly change their activity level. The researchers could demonstrate that characteristic changes in the channels’ dynamics cause these activity shifts. This finding provides a better understanding of eukaryotic voltage-gated potassium channels that are important drug targets for, e.g., cardiovascular or neurological disorders. The study, led by Dr. Markus Weingarth of Utrecht University, is published in Nature Communications today.

“You cannot fully understand how ion channels work without understanding their dynamics,” explains Dr. Markus Weingarth. “Now for the first time, we have been able to quantitatively study the conformational and motional landscape of potassium channels in native-like lipid membranes thanks to an advanced solid-state NMR approach.”

A widespread regulatory mechanism with unknown molecular origin

Ion channels stringently control the flux of ions across cell membranes and are of fundamental importance for all excitable cells. Basically, all classes of ion channels show so-called ‘modal gating behaviour’, which means they spontaneously change their activity level without external stimulus. Despite the fundamental importance of modal gating, its molecular origins are very poorly understood.

Structural information is not enough

Notably, structural data could not explain modal gating behaviour. Intriguingly, mutant channels that are representative for different natively occurring random activity shifts give exactly the same X-ray structures, which resulted in the strangely disparate perspectives of structural similarity and functional heterogeneity.

Shifts in ion channel dynamics cause sudden activity jumps

Using advanced solid-state NMR methods, the researchers could measure the motional landscape of the potassium channel KcsA at high-resolution. Remarkably, states of different activity show highly characteristic dynamics in the so-called selectivity filter, which is an ultra-conserved key element for ion transport and selectivity. These functionally critical changes in the dynamics are triggered by fluctuation in the hydrogen bonding and water network. This level of detailed information on the channel dynamics could only be obtained by combining the NMR insights with computer simulations that were performed by the group of Benoît Roux from the University of Chicago.

Findings provide important clues for eukaryotic potassium channels

“Altogether, this establishes the shifts in the conformational dynamics of the selectivity filter as the key physiological determinant of modal gating shifts in ion channels,” explains Dr. Markus Weingarth. At the same time, this work provides a long-needed quantitative description of the selectivity filter dynamics in a native environment, which is of fundamental importance to understand ion channel function. Given that the filter dynamics are strongly different in mutant channels that mimic voltage-gated potassium channels, this study provides critical clues to better understand eukaryotic potassium channels.

This research was supported by the Netherlands Organization for Scientific Research through their funding of uNMR-NL (project 184.032.201), an NWO-funded Roadmap NMR Facility embedded in the Bijvoet Center. MW acknowledges further support by an NWO VIDI Grant (project 723.014.003).

Publication

Shifts in the selectivity filter dynamics cause modal gating in K+ channels
Shehrazade Jekhmane*, João Medeiros-Silva*, Jing Li, Felix Kümmerer*, Christoph Müller-Hermes*, Marc Baldus*, Benoît Roux, and Markus Weingarth*
Nature Communications 10 January 2019, DOI 10.1038/s41467-018-07973-6
* researchers affiliated with Utrecht University