A propofol binding site in the voltage sensor domain mediates inhibition of HCN1 channel activity.
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Burtscher V, Wang L, Cowgill J, Chen ZW, Edge C, Smith E, Chang Y, Delemotte L, Evers AS, Chanda B
Sci Adv 11 (1) eadr7427 [2025-01-03; online 2025-01-03]
Hyperpolarization-activated and cyclic nucleotide-gated (HCN) ion channels are members of the cyclic nucleotide-binding family and are crucial for regulating cellular automaticity in many excitable cells. HCN channel activation contributes to pain perception, and propofol, a widely used anesthetic, acts as an analgesic by inhibiting the voltage-dependent activity of HCN channels. However, the molecular determinants of propofol action on HCN channels remain unknown. Here, we use a propofol-analog photoaffinity labeling reagent to identify propofol binding sites in the human HCN1 isoform. Mass spectrometry analyses combined with molecular dynamics simulations show that a binding pocket is formed by extracellularly facing residues in the S3 and S4 transmembrane segments in the resting voltage-sensor conformation. Mutations of residues within the putative binding pocket mitigate or eliminate voltage-dependent modulation of HCN1 currents by propofol. Together, these findings reveal a conformation-specific propofol binding site that underlies voltage-dependent inhibition of HCN currents and provides a framework for identifying highly specific modulators of HCN channel gating.
PubMed 39752505
DOI 10.1126/sciadv.adr7427
Crossref 10.1126/sciadv.adr7427