The cryo-EM structure and physical basis for anesthetic inhibition of the THIK1 K2P channel

Area of Science:

• Neuroscience
• Molecular Biology
• Biophysics

Background:

• Microglial surveillance and inflammatory responses are regulated by THIK1 (tandem pore domain potassium channel 1) channels.
• THIK1 channels are implicated in neurodegenerative diseases, making them potential therapeutic targets.
• Understanding THIK1 channel gating and inhibition by volatile anesthetics (VAs) is crucial but poorly understood.

Purpose of the Study:

• To determine the molecular architecture of the THIK1 channel.
• To elucidate the structural basis of THIK1 channel gating and inhibition by VAs.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to obtain high-resolution structure.
• Anesthetic photolabeling experiments.
• Electrophysiology to assess channel function.
• Molecular dynamics simulations.

Main Results:

• A 3.2 Å cryo-EM structure of the closed THIK1 channel was determined.
• A central pore gate, formed by TM4 helix tyrosine residues, was identified below the selectivity filter.
• A critical VA binding site was localized between the central gate and the TM2/TM3 loop, essential for anesthetic inhibition.

Conclusions:

• The study reveals the molecular structure of the THIK1 channel.
• Key structural elements regulating THIK1 gating and VA inhibition have been identified.
• These findings provide a foundation for developing therapeutics targeting THIK1 channels in neurodegenerative diseases.