A propofol binding site in the voltage sensor domain mediates inhibition of HCN1 channel activity.

Summary

Using photoaffinity labeling, mass spectrometry, and molecular dynamics, the authors identify a resting-state binding pocket for propofol in the HCN1 voltage sensor (S3–S4). Mutagenesis within this pocket abrogates propofol’s voltage-dependent inhibition, revealing a conformation-specific site that explains HCN modulation and guides design of selective HCN modulators.

Key Findings

• Photoaffinity labeling identified a propofol binding site in the HCN1 voltage sensor domain.
• MS and MD simulations localized a resting-state pocket formed by extracellular S3–S4 residues.
• Mutating pocket residues abolished voltage-dependent inhibition of HCN1 by propofol.

Clinical Implications

While preclinical, the identified binding pocket explains propofol’s HCN-mediated effects (e.g., analgesia, bradycardia risk) and could inform next-generation agents that modulate HCN gating without off-target effects.

Limitations

• Findings focused on HCN1 isoform; generalizability to other HCN isoforms not directly tested
• No high-resolution structural (e.g., cryo-EM) complex of propofol–HCN1 presented

Future Directions

Solve high-resolution structures of propofol-bound HCN states; test isoform-specificity and in vivo relevance; leverage the pocket to design selective HCN modulators for analgesia and arrhythmia modulation.