Sensitized signalling between L-type Ca2+ channels and ryanodine receptors in the absence or inhibition of FKBP12.6 in cardiomyocytes
Sensitized signalling between L-type Ca2+ channels and ryanodine receptors in the absence or inhibition of FKBP12.6 in cardiomyocytes
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心肌细胞中缺乏或抑制 FKBP12.6 时 L 型 Ca2 通道和兰尼碱受体之间的敏化信号传导
DOI：
10.1093/cvr/cvw247
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发表时间：
2017-01
影响因子：
10.8
通讯作者：
ShiQiang Wang
中科院分区：
文献类型：
--
作者：
YanTing Zhao;YunBo Guo;Lei Gu;XueXin Fan;HuaQian Yang;Zheng Chen;Peng Zhou;Qi Yuan;GuangJu Ji;ShiQiang Wang
目的心肌收缩是由L型钙通道与兰尼碱受体（RyRs）之间的钙诱导钙释放（CICR）控制的。FK 506结合蛋白FKBP12.6与RyR亚基结合，但其在稳定RyR功能中的作用一直存在争议。最近的高分辨率RyR结构的报告表明，HD2结构域，结合FKBP结合RyR 1的相邻亚基的SPRY 2结构域是脱离的，在FKBP无效RyR 2中是不可见的。本研究旨在检测FKBP 12.6缺失对RyR 2原位激活的影响。方法和结果使用全细胞膜片钳技术结合共聚焦成像，我们应用了一个近阈值去极化激活一个非常小的部分LCC，这反过来又激活RyR钙火花随机。FKBP12.6敲除和FK 506/雷帕霉素处理增加了火花频率和LCC-RyR偶联保真度，而不改变LCC开放概率。FK 506和雷帕霉素均未进一步改变FKBP12.6敲除细胞中LCC-RyR偶联的保真度。在松封膜片钳实验中，LCC-RyR信号传导动力学，由LCC sparklet触发RyR火花的延迟指示，在FKBP12.6敲除和FK 506/雷帕霉素处理后加速。这些结果表明，在没有FKBP 12.6的情况下，RyR对Ca 2+触发剂变得更敏感。异丙肾上腺素（1 M）进一步加速FKBP 12.6敲除细胞中的LCC-RyR信号传导。通过儿茶酚胺能信号传导和FKBP 12.6功能障碍对RyR的协同增敏使CICR系统不稳定，导致混乱的Ca 2+波和室性心律失常。总结：FKBP 12.6可防止RyR过度致敏，稳定潜在再生的CICR系统，从而可能抑制危及生命的肿瘤发生。
Aims The heart contraction is controlled by the Ca2+-induced Ca2+ release (CICR) between L-type Ca2+ channels and ryanodine receptors (RyRs). The FK506-binding protein FKBP12.6 binds to RyR subunits, but its role in stabilizing RyR function has been debated for long. Recent reports of high-resolution RyR structure show that the HD2 domain that binds to the SPRY2 domain of neighbouring subunit in FKBP-bound RyR1 is detached and invisible in FKBP-null RyR2. The present study was to test the consequence of FKBP12.6 absence on the in situ activation of RyR2. Methods and results Using whole-cell patch-clamp combined with confocal imaging, we applied a near threshold depolarization to activate a very small fraction of LCCs, which in turn activated RyR Ca2+ sparks stochastically. FKBP12.6-knockout and FK506/rapamycin treatments increased spark frequency and LCC-RyR coupling fidelity without altering LCC open probability. Neither FK506 nor rapamycin further altered LCC-RyR coupling fidelity in FKBP12.6-knockout cells. In loose-seal patch-clamp experiments, the LCC-RyR signalling kinetics, indexed by the delay for a LCC sparklet to trigger a RyR spark, was accelerated after FKBP12.6 knockout and FK506/rapamycin treatments. These results demonstrated that RyRs became more sensitive to Ca2+ triggers without FKBP12.6. Isoproterenol (1 &mgr;M) further accelerated the LCC-RyR signalling in FKBP12.6-knockout cells. The synergistic sensitization of RyRs by catecholaminergic signalling and FKBP12.6 dysfunction destabilized the CICR system, leading to chaotic Ca2+ waves and ventricular arrhythmias. Conclusion: FKBP12.6 keeps the RyRs from over-sensitization, stabilizes the potentially regenerative CICR system, and thus may suppress the life-threatening arrhythmogenesis.
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影响因子：
64.8
作者：
Yan, Zhen;Bai, Xiao-chen;Yan, Chuangye;Wu, Jianping;Li, Zhangqiang;Xie, Tian;Peng, Wei;Yin, Chang-cheng;Li, Xueming;Scheres, Sjors H. W.;Shi, Yigong;Yan, Nieng
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影响因子：
10.8
作者：
通讯作者：
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影响因子：
9.8
作者：
Xu, Ming;Zhou, Peng;Xu, Shi-Ming;Liu, Yin;Feng, Xinheng;Bai, Shu-Hua;Bai, Yan;Hao, Xue-Mei;Han, Qide;Zhang, Youyi;Wang, Shi-Qiang
通讯作者：
Wang, Shi-Qiang
影响因子：
20.1
作者：
E. McCall;L. Li;H. Satoh;T. Shannon;L. Blatter;D. Bers
通讯作者：
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