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

Summary

This cryo-EM study resolves THIK1 in a closed state, identifies a central pore gate formed by TM4 tyrosines, and maps a volatile anesthetic binding site required for inhibition. Multimodal validation links structural gating to anesthetic action on microglial K2P channels.

Key Findings

• A 3.2 Å cryo-EM structure of THIK1 reveals a closed conformation with a central pore gate formed by inward-facing TM4 tyrosines.
• Volatile anesthetic inhibition requires closure of the central pore gate and involves a binding site between the gate and TM2/TM3 loop.
• Photolabeling, electrophysiology, and molecular dynamics consistently validate the anesthetic binding site and gating mechanism.

Clinical Implications

While preclinical, these insights could inform the design of anesthetics or modulators that target microglial function and neuroinflammation, and refine mechanistic models of anesthetic action.

Limitations

• Findings are preclinical and based on purified protein and model systems
• Generalizability to human in vivo anesthetic effects and other K2P channels remains to be established

Future Directions

Test in vivo relevance of the identified binding site and gating mechanism, assess isoform selectivity across K2P family, and explore structure-guided design of anesthetic modulators.