Propofol Restores Voltage-Dependent Gating in HCN1 Channel Epilepsy Mutations

Konsep Inti

Propofol, a general anesthetic, inhibits HCN1 channels by binding to a specific site between the S5 and S6 transmembrane helices, and can restore voltage-dependent closing in two HCN1 epilepsy-associated polymorphisms that destabilize the channel's closed state.

Abstrak

The article investigates the structural basis and mechanism of propofol inhibition of HCN1 channels, which are essential for pacemaking activity and neural signaling. Using single-particle cryo-electron microscopy and electrophysiology, the researchers found that propofol binds to a groove between the S5 and S6 transmembrane helices of the HCN1 channel.

Importantly, the study shows that propofol can restore voltage-dependent closing in two HCN1 epilepsy-associated mutations, M305L and D401H, which act by destabilizing the channel's closed state. By tracking voltage-sensor movement in spHCN channels, the authors determined that propofol inhibition is independent of voltage-sensor conformational changes, suggesting that voltage-dependent closure requires the integrity of the methionine-phenylalanine interface in the S5-S6 region.

The findings provide a structural and mechanistic understanding of how propofol inhibits HCN1 channels and how it can rescue voltage-dependent gating in certain epilepsy-associated mutations. This knowledge could help in the design of specific drugs targeting HCN channelopathies.

Statistik

Propofol inhibits HCN1 channels by binding to a groove between the S5 and S6 transmembrane helices.
Propofol can restore voltage-dependent closing in two HCN1 epilepsy-associated polymorphisms, M305L and D401H, that destabilize the channel's closed state.
Mutations at the homologous methionine in spHCN and an adjacent conserved phenylalanine in S6 similarly destabilize closing without disrupting voltage-sensor movements.

Kutipan

"Propofol inhibits HCN1 by binding to a mechanistic hotspot in a groove between the S5 and S6 transmembrane helices."
"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."
"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."

Wawasan Utama Disaring Dari

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

by Elizabeth D.... pada www.nature.com 07-31-2024

https://www.nature.com/articles/s41586-024-07743-z

Pertanyaan yang Lebih Dalam

How might the insights from this study on propofol's interaction with HCN1 channels be leveraged to develop more targeted and effective treatments for epilepsy and other HCN-related disorders?

The insights gained from this study on propofol's interaction with HCN1 channels provide a foundation for the development of more targeted and effective treatments for epilepsy and other HCN-related disorders. By identifying the specific binding site of propofol on the HCN1 channel and understanding how it restores voltage-dependent gating in epilepsy-associated mutants, researchers can design drugs that specifically target this site to modulate HCN channel activity. This targeted approach could lead to the development of novel therapeutics that selectively regulate HCN channels, offering more precise control over neuronal excitability and potentially reducing the side effects associated with non-specific modulation of ion channels.

What other potential mechanisms or factors, beyond the methionine-phenylalanine interface, could contribute to the voltage-dependent gating of HCN channels that were not explored in this study?

While this study focused on the role of the methionine-phenylalanine interface in voltage-dependent gating of HCN channels, there are other potential mechanisms or factors that could contribute to this process. One such factor could be post-translational modifications of the channel proteins, such as phosphorylation or glycosylation, which are known to influence the function of ion channels. Additionally, interactions with auxiliary subunits or other regulatory proteins could also play a role in modulating the voltage-dependent gating of HCN channels. Exploring these alternative mechanisms in future studies could provide a more comprehensive understanding of the complex regulatory networks that control HCN channel activity.

Given the importance of HCN channels in pacemaking activity and neural signaling, how might the findings from this research on propofol's effects on HCN1 channels inform our understanding of the broader physiological roles of HCN channels in the nervous system?

The findings from this research on propofol's effects on HCN1 channels offer valuable insights into the broader physiological roles of HCN channels in the nervous system. By elucidating the structural basis of propofol inhibition and its restoration of voltage-dependent gating in HCN1 channels, this study enhances our understanding of how HCN channels contribute to pacemaking activity and neural signaling. These insights can inform future investigations into the role of HCN channels in regulating neuronal excitability, synaptic transmission, and network oscillations, providing a deeper understanding of their impact on overall brain function. Furthermore, the identification of a mechanistic hotspot for drug binding on HCN channels opens up new possibilities for developing targeted therapies to modulate HCN channel activity in various neurological disorders.