Zentrum für Experimentelle Medizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
J Physiol. 2011 Feb 1;589(Pt 3):461-79. doi: 10.1113/jphysiol.2010.191965. Epub 2010 Nov 22.
Inactivation of voltage-gated ion channels is an intrinsic auto-regulatory process necessary to govern the occurrence and shape of action potentials and establish firing patterns in excitable tissues. Inactivation may occur from the open state (open-state inactivation, OSI) at strongly depolarized membrane potentials, or from pre-open closed states (closed-state inactivation, CSI) at hyperpolarized and modestly depolarized membrane potentials. Voltage-gated Na(+), K(+), Ca(2+) and non-selective cationic channels utilize both OSI and CSI. Whereas there are detailed mechanistic descriptions of OSI, much less is known about the molecular basis of CSI. Here, we review evidence for CSI in voltage-gated cationic channels (VGCCs) and recent findings that shed light on the molecular mechanisms of CSI in voltage-gated K(+) (Kv) channels. Particularly, complementary observations suggest that the S4 voltage sensor, the S4S5 linker and the main S6 activation gate are instrumental in the installment of CSI in Kv4 channels. According to this hypothesis, the voltage sensor may adopt a distinct conformation to drive CSI and, depending on the stability of the interactions between the voltage sensor and the pore domain, a closed-inactivated state results from rearrangements in the selectivity filter or failure of the activation gate to open. Kv4 channel CSI may efficiently exploit the dynamics of the subthreshold membrane potential to regulate spiking properties in excitable tissues.
电压门控离子通道的失活是一种内在的自动调节过程，对于控制动作电位的发生和形态以及在可兴奋组织中建立发放模式是必要的。失活可以从强去极化膜电位的开放状态（开放状态失活，OSI）发生，也可以从超极化和适度去极化膜电位的预开放关闭状态（关闭状态失活，CSI）发生。电压门控 Na(+)、K(+)、Ca(2+) 和非选择性阳离子通道都利用 OSI 和 CSI。尽管 OSI 有详细的机制描述，但 CSI 的分子基础知之甚少。在这里，我们回顾了电压门控阳离子通道（VGCC）中的 CSI 证据，以及最近关于电压门控 K(+)（Kv）通道 CSI 分子机制的发现。特别是，互补的观察结果表明，S4 电压传感器、S4S5 接头和主要 S6 激活门在 Kv4 通道 CSI 的安装中起着重要作用。根据这一假设，电压传感器可能会采用一种独特的构象来驱动 CSI，并且取决于电压传感器和孔域之间的相互作用的稳定性，选择性过滤器的重排或激活门无法打开会导致失活状态。Kv4 通道 CSI 可以有效地利用亚阈值膜电位的动力学来调节可兴奋组织中的发放特性。
