A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV channels
A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV channels
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DOI：
10.1038/nature06529
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发表时间：
2008-02-14
期刊：
影响因子：
64.8
通讯作者：
Yue, David T.
中科院分区：
文献类型：
--
作者：
Dick, Ivy E.;Tadross, Michael R.;Yue, David T.
电压门控Ca（V）1 - 2Ca 2+通道的Ca 2 +/钙调蛋白依赖性调节显示了空间Ca 2+解码和通道调节的特殊模式（1-6），这对许多生物功能至关重要（6-9）。单个钙调素（CaM）分子与通道的羧基末端尾组成性地结合（3，10 -13），Ca 2+与CaM的C末端和N末端叶的结合可各自诱导不同的通道调节（2，14）.正如从通道附近所预期的那样，C叶响应由相关通道驱动的大约100 μ M的Ca 2+脉冲（15，16），这种行为被定义为“局部Ca 2+选择性”。相反，所有先前的观察都表明N叶以某种方式感知到来自遥远Ca 2+源的弱得多的信号（2，3，17，18）。这种“全局Ca 2+选择性”满足了一般的信号传导要求，使常驻分子能够远程感知细胞Ca 2+活性，否则这将被通过宿主通道的Ca 2+进入所掩盖（5，6）。在这里，我们表明，空间Ca 2+的选择性N叶钙调素的调节并不总是全球性的，但可以通过一个新的Ca 2 +/CaM-结合位点内的氨基末端的通道（NSCaTE，为N-末端空间Ca 2+转化元件）切换。天然的Ca（V）2.2通道缺乏这种元件，显示出N叶调节的全局选择性.在将NSCaTE引入这些通道中时，空间Ca 2+选择性从全局转变为局部分布。考虑到这种效应，我们检查了天然含有NSCaTE的Ca（V）1.2/ Ca（V）1.3通道，发现它们的N叶选择性确实是局部的。该元件的破坏产生全局选择性，证实了NSCaTE的天然功能。因此，晚期Ca（V）1和Ca（V）2通道亚型之间的空间选择性差异可以通过NSCaTE的存在或不存在来解释。除了功能效应，NSCaTE在通道氨基末端的位置表明CaM可以桥接通道的氨基末端和羧基末端。最后，NSCaTE的模块化为理解整体Ca 2+选择性的基础提供了实用的方法（19）。
Ca2+/ calmodulin- dependent regulation of voltage- gated Ca(V)1 - 2 Ca2+ channels shows extraordinary modes of spatial Ca2+ decoding and channel modulation(1-6), vital for many biological functions(6-9). A single calmodulin ( CaM) molecule associates constitutively with the channel's carboxy- terminal tail(3,10-13), and Ca2+ binding to the C- terminal and N- terminal lobes of CaM can each induce distinct channel regulations(2,14). As expected from close channel proximity, the C- lobe responds to the roughly 100-mu M Ca2+ pulses driven by the associated channel(15,16), a behaviour defined as 'local Ca2+ selectivity'. Conversely, all previous observations have indicated that the N- lobe somehow senses the far weaker signals from distant Ca2+ sources(2,3,17,18). This 'global Ca2+ selectivity' satisfies a general signalling requirement, enabling a resident molecule to remotely sense cellular Ca2+ activity, which would otherwise be overshadowed by Ca2+ entry through the host channel(5,6). Here we show that the spatial Ca2+ selectivity of N- lobe CaM regulation is not invariably global but can be switched by a novel Ca2+/CaM- binding site within the amino terminus of channels ( NSCaTE, for N- terminal spatial Ca2+ transforming element). Native Ca(V)2.2 channels lack this element and show N- lobe regulation with a global selectivity. On the introduction of NSCaTE into these channels, spatial Ca2+ selectivity transforms from a global to local profile. Given this effect, we examined Ca(V)1.2/ Ca(V)1.3 channels, which naturally contain NSCaTE, and found that their N- lobe selectivity is indeed local. Disruption of this element produces a global selectivity, confirming the native function of NSCaTE. Thus, differences in spatial selectivity between advanced Ca(V)1 and Ca(V)2 channel isoforms are explained by the presence or absence of NSCaTE. Beyond functional effects, the position of NSCaTE on the channel's amino terminus indicates that CaM can bridge the amino terminus and carboxy terminus of channels. Finally, the modularity of NSCaTE offers practical means for understanding the basis of global Ca2+ selectivity(19).