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TitlePropofol rescues voltage-dependent gating of HCN1 channel epilepsy mutants.
Journal, issue, pagesNature, Vol. 632, Issue 8024, Page 451-459, Year 2024
Publish dateJul 31, 2024
AuthorsElizabeth D Kim / Xiaoan Wu / Sangyun Lee / Gareth R Tibbs / Kevin P Cunningham / Eleonora Di Zanni / Marta E Perez / Peter A Goldstein / Alessio Accardi / H Peter Larsson / Crina M Nimigean /
PubMed AbstractHyperpolarization-activated cyclic nucleotide-gated (HCN) channels are essential for pacemaking activity and neural signalling. Drugs inhibiting HCN1 are promising candidates for management of ...Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are essential for pacemaking activity and neural signalling. Drugs inhibiting HCN1 are promising candidates for management of neuropathic pain and epileptic seizures. The general anaesthetic propofol (2,6-di-iso-propylphenol) is a known HCN1 allosteric inhibitor 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. ). 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.
External linksNature / PubMed:39085604
MethodsEM (single particle)
Resolution2.5 - 3.3 Å
Structure data

42116

8uc7

EMDB-42116, PDB-8uc7:
HCN1 complex with propofol
Method: EM (single particle) / Resolution: 2.9 Å

42117

8uc8

EMDB-42117, PDB-8uc8:
HCN1 nanodisc
Method: EM (single particle) / Resolution: 3.0 Å

44425

9bc6

EMDB-44425, PDB-9bc6:
HCN1 M305L with propofol
Method: EM (single particle) / Resolution: 2.5 Å

44426

9bc7

EMDB-44426, PDB-9bc7:
HCN1 M305L holo
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-PFL:
2,6-BIS(1-METHYLETHYL)PHENOL

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

ChemComp-CMP:
ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN/INHIBITOR / inhibitor / complex / plasma membrane / cyclic nucleotide / TRANSPORT PROTEIN-INHIBITOR complex / TRANSPORT PROTEIN / membrane protein / nanodisc

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