K<sub>2P</sub> channel C-type gating involves asymmetric selectivity filter order-disorder transitions.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33127683.
- Also identified by DOI 10.1126/sciadv.abc9174 and PMC identifier 7608817.
- Licence recorded as CC BY-NC.
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Abstract
K<sub>2P</sub> potassium channels regulate cellular excitability using their selectivity filter (C-type) gate. C-type gating mechanisms, best characterized in homotetrameric potassium channels, remain controversial and are attributed to selectivity filter pinching, dilation, or subtle structural changes. The extent to which such mechanisms control C-type gating of innately heterodimeric K<sub>2P</sub>s is unknown. Here, combining K<sub>2P</sub>2.1 (TREK-1) x-ray crystallography in different potassium concentrations, potassium anomalous scattering, molecular dynamics, and electrophysiology, we uncover unprecedented, asymmetric, potassium-dependent conformational changes that underlie K<sub>2P</sub> C-type gating. These asymmetric order-disorder transitions, enabled by the K<sub>2P</sub> heterodimeric architecture, encompass pinching and dilation, disrupt the S1 and S2 ion binding sites, require the uniquely long K<sub>2P</sub> SF2-M4 loop and conserved "M3 glutamate network," and are suppressed by the K<sub>2P</sub> C-type gate activator ML335. These findings demonstrate that two distinct C-type gating mechanisms can operate in one channel and underscore the SF2-M4 loop as a target for K<sub>2P</sub> channel modulator development.