K201 (JTV519) suppresses spontaneous Ca2+ release and [3H]ryanodine binding to RyR2 irrespective of FKBP12.6 association
K201 (JTV519) suppresses spontaneous Ca2+ release and [3H]ryanodine binding to RyR2 irrespective of FKBP12.6 association
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DOI：
10.1042/bj20070135
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发表时间：
2007-06-15
影响因子：
4.1
通讯作者：
Chen, S. R. Wayne
中科院分区：
文献类型：
--
作者：
Hunt, Donald J.;Jones, Peter P.;Chen, S. R. Wayne
K201（JTV 519）是一种苯并硫氮杂卓衍生物，具有抗心肌炎和心脏保护作用，但其作用机制既复杂又有争议。据信通过增加RyR 2（心脏兰尼碱受体）对FKBP 12.6（12.6 kDa FK 506结合蛋白）的亲和力来稳定RyR 2（心脏兰尼碱受体）的闭合状态[Wehrens，Lehnart，Reiken，Deng，Vest，塞万提斯，Coromilas，Landry和Marks（2004）Science 304，292-296]。在本研究中，我们研究了K201对大鼠心室肌细胞和表达RyR 2的HEK-293细胞（人胚肾细胞）中Ca 2+超载诱导的自发Ca 2+释放的影响，以及FKBP 12.6在K201作用中的作用。我们发现K201以浓度依赖性方式消除心肌细胞自发性Ca 2+释放。用FK 506处理心室肌细胞以使FKBP12.6与RyR 2分离并不影响K201对自发性Ca 2+释放的抑制。类似地，K201能够抑制FK 506处理的共表达RyR 2和FKBP 12.6的HEK-293细胞中的自发Ca 2+释放。此外，K201以相同的效力抑制单独表达RyR 2的HEK-293细胞和共表达RyR 2和FKBP 12.6的细胞中的自发Ca 2+释放。此外，K201抑制[H-3] ryanodine与RyR 2-wt（野生型）和与室性心动过速和猝死相关的RyR 2突变体N4104 K的结合，在不存在FKBP 12.6的情况下。这些观察结果表明，FKBP 12.6不参与K201对自发Ca 2+释放的抑制作用。我们的研究结果还表明，抑制自发Ca 2+释放和RyR 2的活性有助于，至少部分，K201的抗肿瘤特性。
K201 (JTV519), a benzothiazepine derivative, has been shown to possess anti-arrhythmic and cardioprotective properties, but the mechanism of its action is both complex and controversial. It is believed to stabilize the closed state of the RyR2 (cardiac ryanodine receptor) by increasing its affinity for the FKBP12.6 (12.6 kDa FK506 binding protein) [Wehrens, Lehnart, Reiken, Deng, Vest, Cervantes, Coromilas, Landry and Marks (2004) Science 304, 292-296]. In the present study, we investigated the effect of K201 on spontaneous Ca2+ release induced by Ca2+ overload in rat ventricular myocytes and in HEK-293 cells (human embryonic kidney cells) expressing RyR2 and the role of FKBP 12.6 in the action of K201. We found that K201 abolished spontaneous Ca2+ release in cardiac myocytes in a concentration-dependent manner. Treating ventricular myocytes with FK506 to dissociate FKBP12.6 from RyR2 did not affect the suppression of spontaneous Ca2+ release by K201. Similarly, K201 was able to suppress spontaneous Ca2+ release in FK506-treared HEK-293 cells co-expressing RyR2 and FKBP12.6. Furthermore, K201 suppressed spontaneous Ca2+ release in HEK-293 cells expressing RyR2 alone and in cells co-expressing RyR2 and FKBP12.6 with the same potency. In addition, K201 inhibited [H-3] ryanodine binding to RyR2-wt (wild-type) and an RyR2 mutant linked to ventricular tachycardia and sudden death, N4104K, in the absence of FKBP 12.6. These observations demonstrate that FKBP12.6 is not involved in the inhibitory action of K201 on spontaneous Ca2+ release. Our results also suggest that suppression of spontaneous Ca2+ release and the activity of RyR2 contributes, at least in part, to the anti-arrhythmic properties of K201.