Cheng Yen May, Claydon Tom W
Department of Biomedical Physiology and Kinesiology, Simon Fraser University Burnaby, BC, Canada.
Front Pharmacol. 2012 May 8;3:83. doi: 10.3389/fphar.2012.00083. eCollection 2012.
The mechanisms by which voltage-gated channels sense changes in membrane voltage and energetically couple this with opening of the ion conducting pore has been the source of significant interest. In voltage-gated potassium (Kv) channels, much of our knowledge in this area comes from Shaker-type channels, for which voltage-dependent gating is quite rapid. In these channels, activation and deactivation are associated with rapid reconfiguration of the voltage-sensing domain unit that is electromechanically coupled, via the S4-S5 linker helix, to the rate-limiting opening of an intracellular pore gate. However, fast voltage-dependent gating kinetics are not typical of all Kv channels, such as Kv11.1 (human ether-à-go-go related gene, hERG), which activates and deactivates very slowly. Compared to Shaker channels, our understanding of the mechanisms underlying slow hERG gating is much poorer. Here, we present a comparative review of the structure-function relationships underlying activation and deactivation gating in Shaker and hERG channels, with a focus on the roles of the voltage-sensing domain and the S4-S5 linker that couples voltage sensor movements to the pore. Measurements of gating current kinetics and fluorimetric analysis of voltage sensor movement are consistent with models suggesting that the hERG activation pathway contains a voltage independent step, which limits voltage sensor transitions. Constraints upon hERG voltage sensor movement may result from loose packing of the S4 helices and additional intra-voltage sensor counter-charge interactions. More recent data suggest that key amino acid differences in the hERG voltage-sensing unit and S4-S5 linker, relative to fast activating Shaker-type Kv channels, may also contribute to the increased stability of the resting state of the voltage sensor.
电压门控通道感知膜电压变化并将其与离子传导孔的开放进行能量耦合的机制一直是人们关注的焦点。在电压门控钾（Kv）通道中，我们在这一领域的许多知识来自于震颤型通道，其电压依赖性门控相当迅速。在这些通道中，激活和失活与电压感应结构域单元的快速重新配置有关，该单元通过S4-S5连接螺旋与细胞内孔门的限速开放进行机电耦合。然而，快速的电压依赖性门控动力学并非所有Kv通道的典型特征，例如Kv11.1（人类醚-去-去相关基因，hERG），其激活和失活非常缓慢。与震颤通道相比，我们对hERG缓慢门控背后机制的理解要差得多。在这里，我们对震颤通道和hERG通道激活和失活门控的结构-功能关系进行了比较综述，重点关注电压感应结构域和将电压传感器运动与孔耦合的S4-S5连接螺旋的作用。门控电流动力学测量和电压传感器运动的荧光分析与模型一致，这些模型表明hERG激活途径包含一个电压非依赖性步骤，这限制了电压传感器的转变。对hERG电压传感器运动的限制可能源于S4螺旋的松散堆积和电压传感器内额外的反电荷相互作用。最近的数据表明，相对于快速激活的震颤型Kv通道，hERG电压感应单元和S4-S5连接螺旋中的关键氨基酸差异也可能有助于提高电压传感器静息状态的稳定性。
