Calcineurin Controls Voltage-Dependent-Inactivation (VDI) of the Normal and Timothy Cardiac Channels.
Calcineurin Controls Voltage-Dependent-Inactivation (VDI) of the Normal and Timothy Cardiac Channels.
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DOI：
10.1038/srep00366
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发表时间：
2012
影响因子：
4.6
通讯作者：
Atlas, Daphne
中科院分区：
文献类型：
--
作者：
Cohen-Kutner, Moshe;Yahalom, Yfat;Trus, Michael;Atlas, Daphne
Ca 2+进入心脏是由Cav1.2失活严格控制的，其中包括Ca 2+依赖性失活（CDI）和电压依赖性失活（VEP）成分。Timothy综合征是先天性长QT综合征的一种亚型，由Cav1.2 α11.2亚基中的G406 R突变几乎完全消除QT引起。在这里，我们发现，在人α11.2的C-末端尾部的CaN结合位点内的单突变（A1929 P）或双突变（H1926 A-H1927 A），加速了失活速率，并增强了wt和Timothy通道的失活。这些结果确定了CaN结合位点作为长期寻求的心脏通道的VDI调节基序。CaN、环孢素A和FK-506的选择性抑制剂作用于相同的CaN结合位点，从而导致CaN的显著增加和加速失活，进一步支持了这一结论。通过增强VDI的CaN抑制剂逆转增强的交感神经张力可能有利于改善蒂莫西综合征并发症，如长QT和自闭症。
Ca2+-entry in the heart is tightly controlled by Cav1.2 inactivation, which involves Ca2+-dependent inactivation (CDI) and voltage-dependent inactivation (VDI) components. Timothy syndrome, a subtype-form of congenital long-QT syndrome, results from a nearly complete elimination of VDI by the G406R mutation in the α11.2 subunit of Cav1.2. Here, we show that a single (A1929P) or a double mutation (H1926A-H1927A) within the CaN-binding site at the human C-terminal tail of α11.2, accelerate the inactivation rate and enhances VDI of both wt and Timothy channels. These results identify the CaN-binding site as the long-sought VDI-regulatory motif of the cardiac channel. The substantial increase in VDI and the accelerated inactivation caused by the selective inhibitors of CaN, cyclosporine A and FK-506, which act at the same CaN-binding site, further support this conclusion. A reversal of enhanced-sympathetic tone by VDI-enhancing CaN inhibitors could be beneficial for improving Timothy syndrome complications such as long-QT and autism.
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影响因子：
5.5
作者：
Santana, LF;Chase, EG;Greven, R
通讯作者：
Greven, R
DOI：
10.1073/pnas.0511322103
发表时间：
2006-03-07
影响因子：
11.1
作者：
Erxleben, C;Liao, YH;Armstrong, DL
通讯作者：
Armstrong, DL
影响因子：
20.1
作者：
Navedo MF;Cheng EP;Yuan C;Votaw S;Molkentin JD;Scott JD;Santana LF
通讯作者：
Santana LF
DOI：
10.1074/jbc.m111.255273
发表时间：
2011-09-09
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Depil K;Beyl S;Stary-Weinzinger A;Hohaus A;Timin E;Hering S
通讯作者：
Hering S
影响因子：
5.5
作者：
Findlay, I
通讯作者：
Findlay, I