Propofol rescues voltage-dependent gating of HCN1 channel epilepsy mutants.

Autor: Kim ED; Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA., Wu X; Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, USA., Lee S; Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA., Tibbs GR; Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA., Cunningham KP; Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, USA.; School of Life Sciences, University of Westminster, London, UK., Di Zanni E; Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA., Perez ME; Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, USA., Goldstein PA; Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA., Accardi A; Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA.; Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA., Larsson HP; Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, USA. peter.larsson@liu.se.; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden. peter.larsson@liu.se., Nimigean CM; Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA. crn2002@med.cornell.edu.; Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA. crn2002@med.cornell.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Aug; Vol. 632 (8024), pp. 451-459. Date of Electronic Publication: 2024 Jul 31.
DOI: 10.1038/s41586-024-07743-z
Abstrakt: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels 1 are essential for pacemaking activity and neural signalling 2,3 . Drugs inhibiting HCN1 are promising candidates for management of neuropathic pain 4 and epileptic seizures 5 . The general anaesthetic propofol (2,6-di-iso-propylphenol) is a known HCN1 allosteric inhibitor 6 with unknown structural basis. Here, using single-particle cryo-electron microscopy and electrophysiology, we show that propofol inhibits HCN1 by binding to a mechanistic hotspot in a groove between the S5 and S6 transmembrane helices. We found that propofol restored voltage-dependent closing in two HCN1 epilepsy-associated polymorphisms that act by destabilizing the channel closed state: M305L, located in the propofol-binding site in S5, and D401H in S6 (refs.  7,8 ). To understand the mechanism of propofol inhibition and restoration of voltage-gating, we tracked voltage-sensor movement in spHCN channels and found that propofol inhibition is independent of voltage-sensor conformational changes. Mutations at the homologous methionine in spHCN and an adjacent conserved phenylalanine in S6 similarly destabilize closing without disrupting voltage-sensor movements, indicating that voltage-dependent closure requires this interface intact. We propose a model for voltage-dependent gating in which propofol stabilizes coupling between the voltage sensor and pore at this conserved methionine-phenylalanine interface in HCN channels. These findings unlock potential exploitation of this site to design specific drugs targeting HCN channelopathies.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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