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超极化激活阳离子通道门附近的运动。

Movements near the gate of a hyperpolarization-activated cation channel.

作者信息

Rothberg Brad S, Shin Ki Soon, Yellen Gary

机构信息

Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. email:

出版信息

J Gen Physiol. 2003 Nov;122(5):501-10. doi: 10.1085/jgp.200308928. Epub 2003 Oct 13.

Abstract

Hyperpolarization-activated cation (HCN) channels regulate pacemaking activity in cardiac cells and neurons. Like the related depolarization-activated K+ channels (Kv channels), HCN channels use an intracellular activation gate to regulate access to an inner cavity, lined by the S6 transmembrane regions, which leads to the selectivity filter near the extracellular surface. Here we describe two types of metal interactions with substituted cysteines in the S6, which alter the voltage-controlled movements of the gate. At one position (L466), substitution of cysteine in all four subunits allows Cd2+ ions at nanomolar concentration to stabilize the open state (a "lock-open" effect). This effect depends on native histidines at a nearby position (H462); the lock-open effect can be abolished by changing the histidines to tyrosines, or enhanced by changing them to cysteines. Unlike a similar effect in Kv channels, this effect depends on a Cd2+ bridge between 462 and 466 in the same subunit. Cysteine substitution at another position (Q468) produces two effects of Cd2+: both a lock-open effect and a dramatic slowing of channel activation-a "lock-closed" effect. The two effects can be separated, because the lock-open effect depends on the histidine at position 462. The novel lock-closed effect results from stabilization of the closed state by the binding of up to four Cd2+ ions. During the opening conformational change, the S6 apparently moves from one position in which the 468C cysteines can bind four Cd2+ ions, possibly as a cluster of cysteines and cadmium ions near the central axis of the pore, to another position (or flexible range of positions) where either 466C or 468C can bind Cd2+ in association with the histidine at 462.

摘要

超极化激活阳离子(HCN)通道调节心脏细胞和神经元的起搏活动。与相关的去极化激活钾通道(Kv通道)一样,HCN通道利用细胞内激活门来调节进入由S6跨膜区域内衬的内腔,该内腔通向细胞外表面附近的选择性过滤器。在这里,我们描述了S6中取代半胱氨酸的两种金属相互作用类型,它们改变了门的电压控制运动。在一个位置(L466),所有四个亚基中的半胱氨酸取代使纳摩尔浓度的Cd2+离子稳定开放状态(“锁定开放”效应)。这种效应取决于附近位置(H462)的天然组氨酸;通过将组氨酸变为酪氨酸可以消除锁定开放效应,或将它们变为半胱氨酸可以增强该效应。与Kv通道中的类似效应不同,这种效应取决于同一亚基中462和466之间的Cd2+桥。在另一个位置(Q468)的半胱氨酸取代产生了Cd2+的两种效应:锁定开放效应和通道激活的显著减慢——“锁定关闭”效应。这两种效应可以分开,因为锁定开放效应取决于462位的组氨酸。这种新的锁定关闭效应是由多达四个Cd2+离子的结合使关闭状态稳定而产生的。在开放构象变化期间,S6显然从一个位置移动,在该位置468C半胱氨酸可以结合四个Cd2+离子,可能是作为靠近孔中心轴的半胱氨酸和镉离子簇,移动到另一个位置(或灵活的位置范围),在该位置466C或468C可以与462位的组氨酸结合Cd2+。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f016/2229576/74baa3197722/200308928s1.jpg

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