Luminal Ca2+ controls activation of the cardiac ryanodine receptor by ATP.
Luminal Ca2+ controls activation of the cardiac ryanodine receptor by ATP.
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DOI：
10.1085/jgp.201110708
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发表时间：
2012-08
期刊：
影响因子：
--
通讯作者：
Gaburjáková M
中科院分区：
文献类型：
--
作者：
Tencerová B;Zahradníková A;Gaburjáková J;Gaburjáková M
在平面脂质双层中研究了腔Ca ~（2+）、胞浆Ca ~（2+）和胞浆三磷酸腺苷（ATP）对心肌兰尼碱受体（RYR 2）通道激活的协同作用。RYR 2门控活性对ATP的剂量反应在舒张期胞质Ca 2+浓度为100 nM时在一系列管腔Ca 2+浓度下表征，反之亦然，在舒张期管腔Ca 2+浓度为1 mM时在一系列胞质Ca 2+浓度下表征。低水平的管腔Ca 2+（1 mM）显著增加了RYR 2通道对ATP的亲和力，但没有显著激活通道。更高水平的管腔Ca 2+（8-53 mM）通过选择性地增加ATP对RYR 2的最大激活而显著放大ATP对RYR 2活性的影响，而不影响通道对ATP的亲和力。近舒张期胞质Ca 2+水平（<500 nM）大大放大了管腔Ca 2+的作用。胞浆Mg ~（2+）的抑制作用不受管腔Ca ~（2+）的影响。在模型中，管腔和胞质Ca 2+的作用可以通过ATP对RYR 2通道的变构作用的调节来解释。我们的研究结果表明，腔Ca 2+离子增强的RYR 2门控活动的存在下，ATP主要是通过结合到一个明显的亲和力在毫摩尔范围内，超过局部腔Ca 2+可能在心肌细胞变化的腔网站。
The synergic effect of luminal Ca2+, cytosolic Ca2+, and cytosolic adenosine triphosphate (ATP) on activation of cardiac ryanodine receptor (RYR2) channels was examined in planar lipid bilayers. The dose–response of RYR2 gating activity to ATP was characterized at a diastolic cytosolic Ca2+ concentration of 100 nM over a range of luminal Ca2+ concentrations and, vice versa, at a diastolic luminal Ca2+ concentration of 1 mM over a range of cytosolic Ca2+ concentrations. Low level of luminal Ca2+ (1 mM) significantly increased the affinity of the RYR2 channel for ATP but without substantial activation of the channel. Higher levels of luminal Ca2+ (8–53 mM) markedly amplified the effects of ATP on the RYR2 activity by selectively increasing the maximal RYR2 activation by ATP, without affecting the affinity of the channel to ATP. Near-diastolic cytosolic Ca2+ levels (<500 nM) greatly amplified the effects of luminal Ca2+. Fractional inhibition by cytosolic Mg2+ was not affected by luminal Ca2+. In models, the effects of luminal and cytosolic Ca2+ could be explained by modulation of the allosteric effect of ATP on the RYR2 channel. Our results suggest that luminal Ca2+ ions potentiate the RYR2 gating activity in the presence of ATP predominantly by binding to a luminal site with an apparent affinity in the millimolar range, over which local luminal Ca2+ likely varies in cardiac myocytes.
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