Roles of sarcoplasmic reticulum Ca2+ cycling and Na+/Ca2+ exchanger in sinoatrial node pacemaking: Insights from bifurcation analysis of mathematical models
Roles of sarcoplasmic reticulum Ca2+ cycling and Na+/Ca2+ exchanger in sinoatrial node pacemaking: Insights from bifurcation analysis of mathematical models
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DOI：
10.1152/ajpheart.00221.2011
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发表时间：
2012-06-01
影响因子：
4.8
通讯作者：
Shibamoto, Toshishige
中科院分区：
文献类型：
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作者：
Kurata, Yasutaka;Hisatome, Ichiro;Shibamoto, Toshishige
作者：Jiang Jiang，Shibamoto T.肌浆网Ca 2+循环和Na+/Ca 2+交换在窦房结起搏中的作用：来自数学模型分叉分析的见解。Am J Physiol Heart Circ Physiol 302：H2285-H2300，2012.首次发表于2012年3月23日; doi：10.1152/ajpheart.00221.2011.-为了阐明肌浆网（SR）Ca 2+循环和Na+/Ca 2+交换器（NCX）在窦房结（SAN）起搏中的作用，我们将稳定性和分叉分析应用于Maltsev和Lakatta开发的耦合时钟系统模型（Am J Physiol Heart Circ Physiol 296：H594-H615，2009）。平衡点（EP），系统在该点是静止的（即，振荡系统失效）、周期轨道（极限环）以及它们的稳定性被确定为模型参数的函数。检测分叉点的稳定性分析证实了SR Ca 2+泵送速率常数（Pup），NCX密度（k（NCX））和L-型Ca 2+通道电导在以前的参数依赖性数值模拟中报告的系统功能的至关重要性。然而，我们发现，模型细胞不表现出自我维持的自动性SR钙离子释放在任何钳位电压，因此需要进一步调整，以重现振荡的本地钙离子释放和净膜电流实验报告在-10 mV。我们进一步扩展的分叉分析揭示了起搏器系统的重要新功能，这些功能超出了先前的数值模拟，与SR Ca 2+循环和NCX在SAN起搏中的作用有关。具体地，我们发现1）NCX有助于EP不稳定性和在正常自发动作电位放电期间增强整个系统的鲁棒性，同时稳定EP以防止电压钳制下的持续Ca 2+振荡; 2）SR需要相对大的k（NCX）和肌膜下Ca 2+扩散屏障（即，子空间），以促进EP不稳定和增强的鲁棒性;和3）递减P-up或k（NCX）降低了对超极化负荷的整个系统的鲁棒性，因为EP稳定和起搏的停止在超极化偏置电流的较低临界幅度下观察到，这表明SR Ca 2+循环有助于通过调节NCX电流和促进EP不稳定增强整个系统的鲁棒性。
Kurata Y, Hisatome I, Shibamoto T. Roles of sarcoplasmic reticulum Ca2+ cycling and Na+/Ca2+ exchanger in sinoatrial node pacemaking: Insights from bifurcation analysis of mathematical models. Am J Physiol Heart Circ Physiol 302: H2285-H2300, 2012. First published March 23, 2012; doi:10.1152/ajpheart.00221.2011.-To elucidate the roles of sarcoplasmic reticulum (SR) Ca2+ cycling and Na+/Ca2+ exchanger (NCX) in sinoatrial node (SAN) pacemaking, we have applied stability and bifurcation analyses to a coupled-clock system model developed by Maltsev and Lakatta (Am J Physiol Heart Circ Physiol 296: H594-H615, 2009). Equilibrium point (EP) at which the system is stationary (i.e., the oscillatory system fails to function), periodic orbit (limit cycle), and their stability were determined as functions of model parameters. The stability analysis to detect bifurcation points confirmed crucial importance of SR Ca2+ pumping rate constant (Pup), NCX density (k(NCX)), and L-type Ca2+ channel conductance for the system function reported in previous parameter-dependent numerical simulations. We showed, however, that the model cell does not exhibit self-sustained automaticity of SR Ca2+ release at any clamped voltage and therefore needs further tuning to reproduce oscillatory local Ca2+ release and net membrane current reported experimentally at - 10 mV. Our further extended bifurcation analyses revealed important novel features of the pacemaker system that go beyond prior numerical simulations in relation to the roles of SR Ca2+ cycling and NCX in SAN pacemaking. Specifically, we found that 1) NCX contributes to EP instability and enhancement of robustness in the full system during normal spontaneous action potential firings, while stabilizing EPs to prevent sustained Ca2+ oscillations under voltage clamping; 2) SR requires relatively large k(NCX) and subsarcolemmal Ca2+ diffusion barrier (i.e., subspace) to contribute to EP destabilization and enhancement of robustness; and 3) decrementing P-up or k(NCX) decreased the full system robustness against hyperpolarizing loads because EP stabilization and cessation of pacemaking were observed at the lower critical amplitude of hyperpolarizing bias currents, suggesting that SR Ca2+ cycling contributes to enhancement of the full system robustness by modulating NCX currents and promoting EP destabilization.