McCall E, Li L, Satoh H, Shannon T R, Blatter L A, Bers D M
Department of Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, Ill 60153, USA.
Circ Res. 1996 Dec;79(6):1110-21. doi: 10.1161/01.res.79.6.1110.
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.
据报道，FK506结合蛋白（FKBP）与骨骼肌和心肌中的雷诺丁受体密切相关，并可调节分离通道中肌浆网（SR）Ca2+释放通道的门控。FK506可抑制FKBP的活性，从而逆转其对SR Ca2+释放的影响。我们研究了FKBP在加载荧光Ca2+指示剂的完整大鼠心室肌细胞正常收缩和Ca2+瞬变过程中的功能。即使在SR Ca2+负荷和Ca2+电流未改变的情况下，FK506也显著增加了稳态抽搐Ca2+瞬变和收缩幅度，这表明FK506增加了兴奋-收缩（E-C）偶联期间SR Ca2+释放的比例。动作电位有所延长，这与较大的Ca2+瞬变导致更大的内向Na(+)-Ca2+交换电流一致。FK506不影响SR Ca2+摄取，但适度降低了完整细胞中通过Na(+)-Ca2+交换的Ca2+外排（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，通过咖啡因诱导的挛缩评估，FK506在稳态刺激期间导致SR Ca2+含量增加。这可能是由于抑制了通过Na(+)-Ca2+交换的Ca2+外流。FK506还加速了SR Ca2+含量的静息衰减，并使静息Ca2+火花频率增加了约四倍。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变化无关。我们得出结论，FK506增加了正常抽搐期间SR Ca2+释放的比例，并提高了静息期间SR Ca2+释放的速率。FK506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重要的SR稳定作用一致。
