Toward an integrative computational model of the Guinea pig cardiac myocyte.
Toward an integrative computational model of the Guinea pig cardiac myocyte.
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DOI：
10.3389/fphys.2012.00244
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发表时间：
2012
影响因子：
4
通讯作者：
Winslow RL
中科院分区：
文献类型：
--
作者：
Gauthier LD;Greenstein JL;Winslow RL
兴奋-收缩(EC)偶联的局部控制理论认为，钙(Ca~(2+))释放的调节发生在纳米结构域水平，其中单个L型钙通道(LCC)的开放触发共定位于二分体内的兰尼定受体(RyR)小簇的开放。局部控制的结果是，整个细胞的钙瞬变是钙离子通过LCC内流的平滑连续函数。虽然这种所谓的分级释放特性已经被知道了一段时间，但它对心肌细胞整合行为的功能重要性还没有得到充分的认识。我们以前建立了一个基于生物物理学的模型，在这个模型中，LCC和RyR通过并元空间的粗粒度表示来相互作用。该模型使用低维的常微分方程组来捕捉局部控制的关键特征。由于模型的建立紧密地基于局部控制的亚细胞基础，电压依赖的增益和分级的钙离子释放是该模型的主要特征。在目前的工作中，我们将这种分级释放模型结合到先前的豚鼠心室肌细胞电生理学、代谢和等长力产生的模型中。由此产生的综合模型预测了实验观察到的动作电位(AP)形状与钙离子的时间和力瞬变之间的因果关系，这种关系不能用缺乏分级释放特性的模型来解释。模型结果表明，即使是AP形态的相对微小的变化，例如，由于疾病中膜转运体表达的重塑或细胞特性的空间变化，也可能对钙瞬变的时间波形产生重大影响，从而影响组织水平的机电功能。
The local control theory of excitation-contraction (EC) coupling asserts that regulation of calcium (Ca2+) release occurs at the nanodomain level, where openings of single L-type Ca2+ channels (LCCs) trigger openings of small clusters of ryanodine receptors (RyRs) co-localized within the dyad. A consequence of local control is that the whole-cell Ca2+ transient is a smooth continuous function of influx of Ca2+ through LCCs. While this so-called graded release property has been known for some time, its functional importance to the integrated behavior of the cardiac ventricular myocyte has not been fully appreciated. We previously formulated a biophysically based model, in which LCCs and RyRs interact via a coarse-grained representation of the dyadic space. The model captures key features of local control using a low-dimensional system of ordinary differential equations. Voltage-dependent gain and graded Ca2+ release are emergent properties of this model by virtue of the fact that model formulation is closely based on the sub-cellular basis of local control. In this current work, we have incorporated this graded release model into a prior model of guinea pig ventricular myocyte electrophysiology, metabolism, and isometric force production. The resulting integrative model predicts the experimentally observed causal relationship between action potential (AP) shape and timing of Ca2+ and force transients, a relationship that is not explained by models lacking the graded release property. Model results suggest that even relatively subtle changes in AP morphology that may result, for example, from remodeling of membrane transporter expression in disease or spatial variation in cell properties, may have major impact on the temporal waveform of Ca2+ transients, thus influencing tissue level electromechanical function.
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影响因子：
20.1
作者：
BEUCKELMANN, DJ;NABAUER, M;ERDMANN, E
通讯作者：
ERDMANN, E
影响因子：
3.4
作者：
Greenstein, JL;Hinch, R;Winslow, RL
通讯作者：
Winslow, RL
影响因子：
--
作者：
BERS, DM;STIFFEL, VM
通讯作者：
STIFFEL, VM
影响因子：
3.4
作者：
Chudin, E;Goldhaber, J;Kogan, B
通讯作者：
Kogan, B
DOI：
10.1111/j.1540-8167.1996.tb00532.x
发表时间：
1996-04-01
影响因子：
2.7
作者：
Allen, TJA
通讯作者：
Allen, TJA