Version history

{
  "pmid": "39085604",
  "doi": "10.1038/s41586-024-07743-z",
  "abstract": "1. Nature. 2024 Aug;632(8024):451-459. doi: 10.1038/s41586-024-07743-z. Epub 2024\n Jul 31.\n\nPropofol rescues voltage-dependent gating of HCN1 channel epilepsy mutants.\n\nKim ED(#)(1), Wu X(#)(2), Lee S(1), Tibbs GR(1), Cunningham KP(2)(3), Di Zanni \nE(1), Perez ME(2), Goldstein PA(1), Accardi A(1)(4), Larsson HP(5)(6), Nimigean \nCM(7)(8).\n\nAuthor information:\n(1)Department of Anesthesiology, Weill Cornell Medical College, New York, NY, \nUSA.\n(2)Department of Physiology and Biophysics, University of Miami Miller School of \nMedicine, Miami, FL, USA.\n(3)School of Life Sciences, University of Westminster, London, UK.\n(4)Department of Physiology and Biophysics, Weill Cornell Medical College, New \nYork, NY, USA.\n(5)Department of Physiology and Biophysics, University of Miami Miller School of \nMedicine, Miami, FL, USA. peter.larsson@liu.se.\n(6)Department of Biomedical and Clinical Sciences, Linköping University, \nLinköping, Sweden. peter.larsson@liu.se.\n(7)Department of Anesthesiology, Weill Cornell Medical College, New York, NY, \nUSA. crn2002@med.cornell.edu.\n(8)Department of Physiology and Biophysics, Weill Cornell Medical College, New \nYork, NY, USA. crn2002@med.cornell.edu.\n(#)Contributed equally\n\nComment in\n    Epilepsy Curr. 2025 Feb 28;25(3):192-194. doi: 10.1177/15357597251318573.\n\nHyperpolarization-activated cyclic nucleotide-gated (HCN) channels1 are \nessential for pacemaking activity and neural signalling2,3. Drugs inhibiting \nHCN1 are promising candidates for management of neuropathic pain4 and epileptic \nseizures5. The general anaesthetic propofol (2,6-di-iso-propylphenol) is a known \nHCN1 allosteric inhibitor6 with unknown structural basis. Here, using \nsingle-particle cryo-electron microscopy and electrophysiology, we show that \npropofol inhibits HCN1 by binding to a mechanistic hotspot in a groove between \nthe S5 and S6 transmembrane helices. We found that propofol restored \nvoltage-dependent closing in two HCN1 epilepsy-associated polymorphisms that act \nby destabilizing the channel closed state: M305L, located in the \npropofol-binding site in S5, and D401H in S6 (refs. 7,8). To understand the \nmechanism of propofol inhibition and restoration of voltage-gating, we tracked \nvoltage-sensor movement in spHCN channels and found that propofol inhibition is \nindependent of voltage-sensor conformational changes. Mutations at the \nhomologous methionine in spHCN and an adjacent conserved phenylalanine in S6 \nsimilarly destabilize closing without disrupting voltage-sensor movements, \nindicating that voltage-dependent closure requires this interface intact. We \npropose a model for voltage-dependent gating in which propofol stabilizes \ncoupling between the voltage sensor and pore at this conserved \nmethionine-phenylalanine interface in HCN channels. These findings unlock \npotential exploitation of this site to design specific drugs targeting HCN \nchannelopathies.\n\n© 2024. The Author(s), under exclusive licence to Springer Nature Limited.\n\nDOI: 10.1038/s41586-024-07743-z\nPMCID: PMC11634041\nPMID: 39085604 [Indexed for MEDLINE]\n\nConflict of interest statement: Competing interest declaration GT and PG are \nco-inventors on patents related to the development of novel alkylphenols for the \ntreatment of neuropathic pain. GT and PG serve on the Scientific Advisory Board \nfor Akelos Inc. (New York, NY), a research-based biotechnology company that has \na licensing agreement for the use of those patents.",
  "journal": "Nature",
  "year": 2024,
  "authors": "Kim ED, Wu X, Lee S, Tibbs GR, Cunningham KP, Di Zanni E, Perez ME, Goldstein PA, Accardi A, Larsson HP",
  "url": "https://pubmed.ncbi.nlm.nih.gov/39085604",
  "external_ids": {
    "doi": "10.1038/s41586-024-07743-z",
    "pmid": "39085604"
  },
  "citation_count": 1,
  "domain": "neurodegeneration"
}