A propofol binding site in the voltage sensor domain mediates inhibition of HCN1 channel activity Article Swipe
Verena Burtscher
,
Lei Wang
,
John Cowgill
,
Zi-Wei Chen
,
Christopher Edge
,
Edward H. Smith
,
Yongchang Chang
,
Lucie Delemotte
,
Alex S. Evers
,
Baron Chanda
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1126/sciadv.adr7427
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1126/sciadv.adr7427
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.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1126/sciadv.adr7427
- OA Status
- gold
- Cited By
- 3
- References
- 58
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4406027985
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4406027985Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1126/sciadv.adr7427Digital Object Identifier
- Title
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A propofol binding site in the voltage sensor domain mediates inhibition of HCN1 channel activityWork title
- Type
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articleOpenAlex work type
- Language
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
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2025-01-03Full publication date if available
- Authors
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Verena Burtscher, Lei Wang, John Cowgill, Zi-Wei Chen, Christopher Edge, Edward H. Smith, Yongchang Chang, Lucie Delemotte, Alex S. Evers, Baron ChandaList of authors in order
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https://doi.org/10.1126/sciadv.adr7427Publisher landing page
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YesWhether a free full text is available
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goldOpen access status per OpenAlex
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https://doi.org/10.1126/sciadv.adr7427Direct OA link when available
- Concepts
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Chemistry, Binding site, Propofol, Biophysics, Gating, Ion channel, Biochemistry, Biology, Pharmacology, ReceptorTop concepts (fields/topics) attached by OpenAlex
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3Total citation count in OpenAlex
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2025: 3Per-year citation counts (last 5 years)
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58Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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| referenced_works | https://openalex.org/W2161201932, https://openalex.org/W3173456444, https://openalex.org/W2154420009, https://openalex.org/W2010973571, https://openalex.org/W1978494722, https://openalex.org/W2087403500, https://openalex.org/W1970353390, https://openalex.org/W2038010997, https://openalex.org/W2094927594, https://openalex.org/W2014619474, https://openalex.org/W2118621245, https://openalex.org/W2144299211, https://openalex.org/W1978471509, https://openalex.org/W2757842300, https://openalex.org/W2129384091, https://openalex.org/W2009176915, https://openalex.org/W2132346701, https://openalex.org/W4385690379, https://openalex.org/W2016371604, https://openalex.org/W1974119455, https://openalex.org/W1572598901, https://openalex.org/W2084398419, https://openalex.org/W2123797085, https://openalex.org/W2576780822, https://openalex.org/W4402495909, https://openalex.org/W4401172123, https://openalex.org/W2883011012, https://openalex.org/W2991264362, https://openalex.org/W4205616329, https://openalex.org/W2100231995, https://openalex.org/W2088909919, https://openalex.org/W2152959849, https://openalex.org/W2911596600, https://openalex.org/W2162174253, https://openalex.org/W1973811079, https://openalex.org/W2148598721, https://openalex.org/W2003387609, https://openalex.org/W3175661216, https://openalex.org/W4399766728, https://openalex.org/W1972584910, https://openalex.org/W1972473633, https://openalex.org/W3082691473, https://openalex.org/W2089367180, https://openalex.org/W2324751055, https://openalex.org/W3173579119, https://openalex.org/W1970650210, https://openalex.org/W2951862048, https://openalex.org/W3159092799, https://openalex.org/W2021520922, https://openalex.org/W2206954826, https://openalex.org/W2066414494, https://openalex.org/W2109154308, https://openalex.org/W2070753604, https://openalex.org/W2990114831, https://openalex.org/W2017196167, https://openalex.org/W2081693079, https://openalex.org/W2067174909, https://openalex.org/W2128572087 |
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| corresponding_author_ids | https://openalex.org/A5088162073, https://openalex.org/A5010876726, https://openalex.org/A5013341660, https://openalex.org/A5100435929 |
| countries_distinct_count | 5 |
| institutions_distinct_count | 10 |
| corresponding_institution_ids | https://openalex.org/I1318643470, https://openalex.org/I204465549, https://openalex.org/I47720641 |
| citation_normalized_percentile.value | 0.91696115 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | True |