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Updated: Sep 3, 2025

High-throughput Screening for Small-molecule Modulators of Inward Rectifier Potassium Channels
Published on: January 27, 2013
General Pharmacological Activation Mechanism of K+ Channels Bypassing Channel Gates
Shijie Liu1, Peipei Guo1, Kun Wang1
1Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Abstract:
Under the known pharmacological activation mechanisms, activators allosterically or directly open potassium channel gates. However, herein, molecular dynamics simulations on TREK-1, a member of the channel class gated at the filter, suggested that negatively charged activators act with a gate-independent mechanism where compounds increase currents by promoting ions passing through the central cavity. Then, based on studies of KCNQ2, we uncovered that this noncanonical activation mechanism is shared by the other channel class gated at the helix-bundle crossing. Rational drug design found a novel KCNQ2 agonist, CLE030, which stably binds to the central cavity. Functional analysis, molecular dynamics simulations, and calculations of the potential of mean force revealed that the carbonyl oxygen of CLE030 influences permeant ions in the central cavity to contribute to its activation effects. Together, this study discovered a ligand-to-ion activation mechanism for channels that bypasses their gates and thus is conserved across subfamilies with different gates.
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