CaMKII tethers to L-type Ca2+ channels, establishing a local and dedicated integrator of Ca2+ signals for facilitation.
CaMKII tethers to L-type Ca2+ channels, establishing a local and dedicated integrator of Ca2+ signals for facilitation.
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CAMKII将Ca2+通道的camkii tethers建立，建立了Ca2+信号的本地和专用集成商进行便利。
DOI：
10.1083/jcb.200505155
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发表时间：
2005-11-07
影响因子：
7.8
通讯作者：
Pitt, GS
中科院分区：
文献类型：
--
作者：
Hudmon, A;Schulman, H;Kim, J;Maltez, JM;Tsien, RW;Pitt, GS
电压门控性钙电流的钙依赖性易化（CDF）是细胞膜反复去极化过程中钙内流上调的重要机制。L型钙通道（Cav1.2）的CDF有助于心脏中的正性力-频率效应，并且被认为涉及钙/钙调蛋白依赖性激酶II（CaMKII）的激活。CaMKII是如何被激活的以及它的底物是什么尚未确定。我们发现，成孔亚基α1C（Cavα1.2）是CaMK Ⅱ的底物，CaMK Ⅱ与α1C的COOH末端的相互作用对于L型通道的CDF是必不可少的。Ca 2+内流触发CaMKII靶向和活性的不同特征。在Ca 2+诱导靶向α1C后，CaMKII变得与通道紧密相连，即使在钙恢复到正常水平后也是如此。相反，栓系的CaMKII的活性仍然完全依赖于Ca 2 +/CaM，这解释了其作为钙峰频率检测器操作的能力。这些发现阐明了CDF的分子基础，并证明了一种新的酶机制，通过这种机制，离子通道门控可以通过活性来调节。
Ca2+-dependent facilitation (CDF) of voltage-gated calcium current is a powerful mechanism for up-regulation of Ca2+ influx during repeated membrane depolarization. CDF of L-type Ca2+ channels (Cav1.2) contributes to the positive force–frequency effect in the heart and is believed to involve the activation of Ca2+/calmodulin-dependent kinase II (CaMKII). How CaMKII is activated and what its substrates are have not yet been determined. We show that the pore-forming subunit α1C (Cavα1.2) is a CaMKII substrate and that CaMKII interaction with the COOH terminus of α1C is essential for CDF of L-type channels. Ca2+ influx triggers distinct features of CaMKII targeting and activity. After Ca2+-induced targeting to α1C, CaMKII becomes tightly tethered to the channel, even after calcium returns to normal levels. In contrast, activity of the tethered CaMKII remains fully Ca2+/CaM dependent, explaining its ability to operate as a calcium spike frequency detector. These findings clarify the molecular basis of CDF and demonstrate a novel enzymatic mechanism by which ion channel gating can be modulated by activity.
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影响因子：
56.9
作者：
De Koninck, P;Schulman, H
通讯作者：
Schulman, H
影响因子：
5
作者：
DeSantiago, J;Maier, LS;Bers, DM
通讯作者：
Bers, DM
影响因子：
5.3
作者：
Eshete, F;Fields, RD
通讯作者：
Fields, RD
影响因子：
3.3
作者：
HAROOTUNIAN, AT;ADAMS, SR;TSIEN, RY
通讯作者：
TSIEN, RY
影响因子：
--
作者：
HRYSHKO, LV;BERS, DM
通讯作者：
BERS, DM