KCNQ2通道S4-S5连接子癫痫相关突变的生物物理和结构机制

Channels (Austin, Tex.) Pub Date : 2025-12-01 Epub Date: 2025-02-19 DOI:10.1080/19336950.2025.2464735
Inn-Chi Lee, Yen-Yu Yang, Hsueh-Kai Chang, Swee-Hee Wong, Shi-Bing Yang
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引用次数: 0

摘要

KCNQ2突变与多种神经系统疾病有关,包括新生儿癫痫。这些情况的严重程度通常与突变的位置和改变的氨基酸侧链的生化特性有关。在KCNQ2的S4-S5连接体中,两个影响天冬氨酸位点212 (D212)的突变已经被发现。有趣的是,当电荷保守的D212E突变导致严重的新生儿发病发育性和癫痫性脑病(DEE)时,更剧烈的甘氨酸替代(D212G)导致自限性家族性新生儿癫痫(SLFNE),这是一种更轻微的病理。为了阐明潜在的机制,我们进行了电生理研究和计算机模拟来研究这些突变的生物物理和结构效应。我们的研究结果表明,D212E突变稳定了电压传感器下状态的通道,破坏了上状态的通道,导致电压依赖的激活曲线向右移动,激活动力学变慢,失活动力学加速。这种KCNQ2电压敏感性的破坏甚至在与生理更相关的KCNQ2/3异四聚体通道中也存在。相比之下,D212G突变主要破坏上态的稳定,但在KCNQ2/3异四聚体通道中,其对电压敏感性的影响显著降低。这些发现为KCNQ2 D212突变的生物物理和结构基础及其对癫痫相关症状的贡献提供了关键见解,并为这些突变如何驱动患者观察到的各种临床结果提供了更清晰的理解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Biophysical and structural mechanisms of epilepsy-associated mutations in the S4-S5 Linker of KCNQ2 channels.

Mutations in KCNQ2 are linked to various neurological disorders, including neonatal-onset epilepsy. The severity of these conditions often correlates with the mutation's location and the biochemical properties of the altered amino acid side chains. Two mutations affecting aspartate at position 212 (D212) in the S4-S5 linker of KCNQ2 have been identified. Interestingly, while the charge-conserved D212E mutation leads to severe neonatal-onset developmental and epileptic encephalopathy (DEE), the more dramatic substitution to glycine (D212G) results in self-limited familial neonatal epilepsy (SLFNE), a much milder pathology. To elucidate the underlying mechanisms, we performed electrophysiological studies and in silico simulations to investigate these mutations' biophysical and structural effects. Our findings reveal that the D212E mutation stabilizes the channel in the voltage sensor down-state and destabilizes the up-state, leading to a rightward shift in the voltage-dependent activation curve, slower activation kinetics, and accelerated deactivation kinetics. This disruption in KCNQ2 voltage sensitivity persists even in the more physiologically relevant KCNQ2/3 heterotetrameric channels. In contrast, the D212G mutation primarily destabilizes the up-state, but its impact on voltage sensitivity is significantly reduced in KCNQ2/3 heterotetrameric channels. These findings provide key insights into the biophysical and structural basis of KCNQ2 D212 mutations and their contribution to epilepsy-related symptoms, offering a clearer understanding of how these mutations drive the varied clinical outcomes observed in patients.

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