Membrane phospholipids control gating of the mechanosensitive potassium leak channel TREK1

Philipp A. M. Schmidpeter, John T. Petroff, Leila Khajoueinejad, Aboubacar Wague, Cheryl Frankfater, Wayland W. L. Cheng, Crina M. Nimigean and Paul M. Riegelhaupt ()
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Philipp A. M. Schmidpeter: Weill Cornell Medical College
John T. Petroff: Washington University School of Medicine in St. Louis
Leila Khajoueinejad: Weill Cornell Medical College
Aboubacar Wague: Weill Cornell Medical College
Cheryl Frankfater: Washington University School of Medicine in St. Louis
Wayland W. L. Cheng: Washington University School of Medicine in St. Louis
Crina M. Nimigean: Weill Cornell Medical College
Paul M. Riegelhaupt: Weill Cornell Medical College

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Tandem pore domain (K2P) potassium channels modulate resting membrane potentials and shape cellular excitability. For the mechanosensitive subfamily of K2Ps, the composition of phospholipids within the bilayer strongly influences channel activity. To examine the molecular details of K2P lipid modulation, we solved cryo-EM structures of the TREK1 K2P channel bound to either the anionic lipid phosphatidic acid (PA) or the zwitterionic lipid phosphatidylethanolamine (PE). At the extracellular face of TREK1, a PA lipid inserts its hydrocarbon tail into a pocket behind the selectivity filter, causing a structural rearrangement that recapitulates mutations and pharmacology known to activate TREK1. At the cytoplasmic face, PA and PE lipids compete to modulate the conformation of the TREK1 TM4 gating helix. Our findings demonstrate two distinct pathways by which anionic lipids enhance TREK1 activity and provide a framework for a model that integrates lipid gating with the effects of other mechanosensitive K2P modulators.

Date: 2023
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DOI: 10.1038/s41467-023-36765-w

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