Effects of FK-506 on contraction and Ca2+ transients in rat cardiac myocytes.
Effects of FK-506 on contraction and Ca2+ transients in rat cardiac myocytes.
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DOI：
10.1161/01.res.79.6.1110
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发表时间：
1996-12
影响因子：
20.1
通讯作者：
E. McCall;L. Li;H. Satoh;T. Shannon;L. Blatter;D. Bers
中科院分区：
文献类型：
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作者：
E. McCall;L. Li;H. Satoh;T. Shannon;L. Blatter;D. Bers
据报道，FK-506 结合蛋白 (FKBP) 与骨骼肌和心肌中的兰尼碱受体密切相关，并调节孤立通道中的肌浆网 (SR) Ca2+ 释放通道门控。 FK-506 可以抑制 FKBP 的活性，从而逆转其对 SR Ca2+ 释放的影响。我们研究了装载荧光 Ca2+ 指示剂的完整大鼠心室肌细胞正常收缩和 Ca2+ 瞬变过程中 FKBP 的功能。即使在 SR Ca2+ 负荷和 Ca2+ 电流不变的情况下，FK-506 也能显着增加稳态抽搐 Ca2+ 瞬变和收缩幅度，这表明 FK-506 增加了兴奋-收缩 (E-C) 耦合过程中释放的 SR Ca2+ 分数。动作电位有所延长，与较大的 Ca2+ 瞬变导致更大的内向 Na(+)-Ca2+ 交换电流一致。 FK-506 不影响 SR Ca2+ 摄取，但通过完整细胞中 Na(+)-Ca2+ 交换适度减少 Ca2+ 排出（尽管在肌膜囊泡中未观察到对 Na(+)-Ca2+ 交换的影响）。在大多数细胞中，FK-506 在稳态刺激期间导致 SR Ca2+ 含量增加（通过咖啡因诱导的挛缩进行评估）。这可能是由于 Na(+)-Ca2+ 交换抑制了 Ca2+ 外流。 FK-506 还加速了 SR Ca2+ 含量的静止衰减，并将静止 Ca2+ 火花的频率增加了约四倍。这些基本 Ca2+ 释放事件频率的增加与 Ca2+ 火花的幅度或持续时间的变化无关。我们得出的结论是，FK-506 增加了正常抽搐期间释放的 SR Ca2+ 比例，并提高了休息期间 SR Ca2+ 释放的速率。 FK-506 还抑制 Na(+)-Ca2+ 交换，尽管这种作用可能是间接的。这些作用与 FKBP 在完整大鼠心室肌细胞中的重要 SR 稳定作用一致。
FK-506 binding protein (FKBP) has been reported to be closely associated with the ryanodine receptor in skeletal and cardiac muscle and to modulate sarcoplasmic reticulum (SR) Ca2+ release channel gating in isolated channels. FK-506 can inhibit the activity of FKBP, thereby reversing its effects on SR Ca2+ release. We investigated the function of FKBP during normal contractions and Ca2+ transients in intact rat ventricular myocytes loaded with fluorescent Ca2+ indicators. FK-506 significantly increased steady state twitch Ca2+ transients and contraction amplitudes even under conditions in which the SR Ca2+ load and Ca2+ current were unaltered, suggesting that FK-506 increases the fraction of SR Ca2+ released during excitation-contraction (E-C) coupling. Action potentials were somewhat prolonged, consistent with the larger Ca2+ transients causing greater inward Na(+)-Ca2+ exchange current. FK-506 did not affect SR Ca2+ uptake but modestly decreased Ca2+ extrusion via Na(+)-Ca2+ exchange in intact cells (although no effect on Na(+)-Ca2+ exchange was seen in sarcolemmal vesicles). In most cells, FK-506 caused an increase in SR Ca2+ content during steady state stimulation, as assessed by caffeine-induced contractures. This was probably due to the inhibition of Ca2+ efflux via Na(+)-Ca2+ exchange. FK-506 also accelerated the rest decay of SR Ca2+ content and increased the frequency of resting Ca2+ sparks about fourfold. The increase in frequency of these basic Ca2+ release events was not associated with changes in the amplitude or duration of the Ca2+ sparks. We conclude that FK-506 increases the fraction of SR Ca2+ released during normal twitches and enhances the rate of SR Ca2+ release during rest. FK-506 also inhibits Na(+)-Ca2+ exchange, although this effect may be indirect. These effects are consistent with an important SR-stabilizing effect of FKBP in intact rat ventricular myocytes.