Multiple pore conformations driven by asynchronous movements of voltage sensors in a eukaryotic sodium channel.
Multiple pore conformations driven by asynchronous movements of voltage sensors in a eukaryotic sodium channel.
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DOI：
10.1038/ncomms2356
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发表时间：
2013
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
电压依赖的Na+通道对可兴奋细胞的电信号至关重要。膜去极化启动在Na+通道的四个不相同的电压感应域的异步运动。与向外纠偏的K+通道相比，目前尚不清楚这种结构不对称在多大程度上影响了孔门，在向外纠偏的K+通道中，通道的打开是由对称孔门的最终协调过渡造成的。在这里，我们结合单通道记录、半胱氨酸可及性和电压钳荧光法来探测失活缺陷Nav1.4通道中电压传感器与孔隙构象之间的关系。我们观察到三种不同的电导水平，因此，DI-III电压传感器的激活与完全开放孔隙的形成在动力学上相关，而DIV电压传感器的运动是在野生型通道失活之前形成独特的亚导电孔隙构象的基础。我们的实验表明，钠通道中的孔门控涉及由电压传感器的异步运动驱动的多个转变。这些发现揭示了电压门控钠通道激活和快速失活耦合的机制。在向外整流钾通道中，去极化引发了电压感应域的构象变化。Goldschen-Ohm等人发现三个特定结构域的移动与电导水平相关，第四个结构域的重排导致失活前的亚电导状态。
Voltage-dependent Na+ channels are crucial for electrical signalling in excitable cells. Membrane depolarization initiates asynchronous movements in four non-identical voltage-sensing domains of the Na+ channel. It remains unclear to what extent this structural asymmetry influences pore gating as compared with outwardly rectifying K+ channels, where channel opening results from a final concerted transition of symmetric pore gates. Here we combine single channel recordings, cysteine accessibility and voltage clamp fluorimetry to probe the relationships between voltage sensors and pore conformations in an inactivation deficient Nav1.4 channel. We observe three distinct conductance levels such that DI-III voltage sensor activation is kinetically correlated with formation of a fully open pore, whereas DIV voltage sensor movement underlies formation of a distinct subconducting pore conformation preceding inactivation in wild-type channels. Our experiments reveal that pore gating in sodium channels involves multiple transitions driven by asynchronous movements of voltage sensors. These findings shed new light on the mechanism of coupling between activation and fast inactivation in voltage-gated sodium channels. In outwardly rectifying potassium channels, depolarization initiates conformational changes in voltage-sensing domains. Goldschen-Ohm et al. find that movement of three specific domains correlates with conductance levels, and rearrangements of a fourth domain results in preinactivation subconductance states.
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影响因子：
16.2
作者：
CHAHINE, M;GEORGE, AL;HORN, R
通讯作者：
HORN, R
影响因子：
4.5
作者：
Jurkat-Rott, Karin;Holzherr, Boris;Fauler, Michael;Lehmann-Horn, Frank
通讯作者：
Lehmann-Horn, Frank
影响因子：
16.2
作者：
EAHOLTZ, G;SCHEUER, T;CATTERALL, WA
通讯作者：
CATTERALL, WA
影响因子：
56.9
作者：
HOSHI, T;ZAGOTTA, WN;ALDRICH, RW
通讯作者：
ALDRICH, RW
影响因子：
4.8
作者：
Kellenberger, S;Scheuer, T;Catterall, WA
通讯作者：
Catterall, WA