Why the study?
Known pharmacological potassium channel activators allosterically or directly open channel gates, but whether noncanonical gate-independent activation mechanisms exist remained to be determined.
This study identifies a novel, gate-independent pharmacological activation mechanism for potassium channels, providing a new paradigm for rational drug design.
Novel KCNQ2 activation mechanism shown in animals; leaves open translation to human channelopathies and drug development.
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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Liu et al. (2022) studied this question.
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