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

ABSTRACT: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels¹ are essential for pacemaking activity and neural signalling^2,3. Drugs inhibiting HCN1 are promising candidates for management of neuropathic pain⁴ and epileptic seizures⁵. The general anaesthetic propofol (2,6-di-iso-propylphenol) is a known HCN1 allosteric inhibitor⁶ 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 i

SUBMITTER: Kim ED 

PROVIDER: S-EPMC11634041 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature