Smith G D, Keizer J E, Stern M D, Lederer W J, Cheng H
Mathematical Research Branch, National Institutes of Health, Bethesda, Maryland 20814, USA.
Biophys J. 1998 Jul;75(1):15-32. doi: 10.1016/S0006-3495(98)77491-0.
The elementary events of excitation-contraction coupling in heart muscle are Ca2+ sparks, which arise from one or more ryanodine receptors in the sarcoplasmic reticulum (SR). Here a simple numerical model is constructed to explore Ca2+ spark formation, detection, and interpretation in cardiac myocytes. This model includes Ca2+ release, cytosolic diffusion, resequestration by SR Ca2+-ATPases, and the association and dissociation of Ca2+ with endogenous Ca2+-binding sites and a diffusible indicator dye (fluo-3). Simulations in a homogeneous, isotropic cytosol reproduce the brightness and the time course of a typical cardiac Ca2+ spark, but underestimate its spatial size (approximately 1.1 micron vs. approximately 2.0 micron). Back-calculating [Ca2+]i by assuming equilibrium with indicator fails to provide a good estimate of the free Ca2+ concentration even when using blur-free fluorescence data. A parameter sensitivity study reveals that the mobility, kinetics, and concentration of the indicator are essential determinants of the shape of Ca2+ sparks, whereas the stationary buffers and pumps are less influential. Using a geometrically more complex version of the model, we show that the asymmetric shape of Ca2+ sparks is better explained by anisotropic diffusion of Ca2+ ions and indicator dye rather than by subsarcomeric inhomogeneities of the Ca2+ buffer and transport system. In addition, we examine the contribution of off-center confocal sampling to the variance of spark statistics.
心肌兴奋 - 收缩偶联的基本事件是钙火花，其源于肌浆网（SR）中的一个或多个兰尼碱受体。在此构建了一个简单的数值模型，以探索心肌细胞中钙火花的形成、检测和解读。该模型包括钙释放、胞质扩散、SR钙 - ATP酶的再摄取以及钙与内源性钙结合位点和可扩散指示染料（fluo - 3）的结合和解离。在均匀、各向同性的胞质溶胶中的模拟重现了典型心脏钙火花的亮度和时间进程，但低估了其空间大小（约1.1微米对约2.0微米）。即使使用无模糊荧光数据，通过假设与指示剂平衡来反算[Ca2 +]i也无法很好地估计游离钙浓度。参数敏感性研究表明，指示剂的迁移率、动力学和浓度是钙火花形状的关键决定因素，而固定缓冲剂和泵的影响较小。使用该模型的几何结构更复杂的版本，我们表明钙火花的不对称形状更好地由钙离子和指示染料的各向异性扩散来解释，而不是由钙缓冲和运输系统的肌小节下不均匀性来解释。此外，我们研究了偏心共聚焦采样对火花统计方差的贡献。
