导语：近日，一项研究揭示了常用麻醉药物丙泊酚如何修复与癫痫相关的HCN1通道突变体的电压门控功能，为治疗HCN通道病提供了新的思路。让我们一起来看看这项激动人心的发现。
摘要译文(供参考)
一、HCN1通道的重要性
HCN（超极化激活环核苷酸门控）通道在神经信号传递和节律活动方面发挥着至关重要的作用。它们是神经系统和心脏起搏活动的关键调节器。近年来，针对HCN1通道的药物被认为是治疗神经性疼痛和癫痫发作的潜力股。
二、丙泊酚的作用机制
丙泊酚，一种广泛使用的全身麻醉药物，被已知能够抑制HCN1通道，但其具体作用机制尚不明确。本研究通过单颗粒冷冻电镜和电生理学技术，揭示了丙泊酚通过结合到S5和S6跨膜螺旋之间的一个机械热点来抑制HCN1通道。
三、修复癫痫相关突变体的电压门控
研究发现，丙泊酚能够修复两种与癫痫相关的HCN1通道多态性突变体的电压门控功能。这两种突变体分别是位于S5中丙泊酚结合位点的M305L和位于S6的D401H。这些突变通过不稳定通道的关闭状态来影响其功能。
四、电压门控机制的深入理解
研究团队通过追踪spHCN通道中的电压传感器运动，发现丙泊酚的抑制作用与电压传感器构象变化无关。在spHCN通道中相应位置的突变和S6中的一个保守苯丙氨酸的突变同样会不稳定关闭状态，但不会破坏电压传感器的运动，这表明电压依赖性关闭需要这个界面的完整性。
五、新型药物设计的启示
研究提出了一个电压门控模型，其中丙泊酚在HCN通道的这个保守的甲硫氨酸-苯丙氨酸界面上稳定电压传感器和孔的耦合。这一发现为设计针对HCN通道病的特异性药物提供了新的靶点。
结语：
这项研究不仅揭示了丙泊酚抑制HCN1通道的分子机制，还为治疗由HCN通道突变引起的癫痫等疾病提供了新的治疗策略。未来，科学家们可能会基于这一发现，开发出更有效、更安全的药物，为患者带来希望。
参考文献：
[1] HCN channels in neurological disease
[2] The role of HCN channels in pacemaker activity
[3] Neural signalling and HCN channels
[4] HCN1 inhibitors for neuropathic pain management
[5] HCN1 inhibitors for epileptic seizures
[6] Propofol as an HCN1 allosteric inhibitor
[7] HCN1 M305L epilepsy-associated polymorphism
[8] HCN1 D401H epilepsy-associated polymorphism
Propofol rescues voltage-dependent gating of HCN1 channel epilepsy mutants
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels1 are essential for pacemaking activity and neural signalling2,3. 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 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.
