Findlay Ian, Suzuki Shingo, Murakami Shingo, Kurachi Yoshihisa
CNRS UMR 6542, Faculté des Sciences, Université François-Rabelais de Tours, France.
Prog Biophys Mol Biol. 2008 Jan-Apr;96(1-3):482-98. doi: 10.1016/j.pbiomolbio.2007.07.002. Epub 2007 Aug 1.
The inactivation of the L-type Ca2+ current is composed of voltage-dependent and calcium-dependent mechanisms. The relative contribution of these processes is still under dispute and the idea that the voltage-dependent inactivation could be subject to further modulation by other physiological processes had been ignored. This study sought to model physiological modulation of inactivation of the current in cardiac ventricular myocytes, based upon the recent detailed experimental data that separated total and voltage-dependent inactivation (VDI) by replacing extracellular Ca2+ with Mg2+ and monitoring L-type Ca2+ channel behaviour by outward K+ current flowing through the channel in the absence of inward current flow. Calcium-dependent inactivation (CDI) was based upon Ca2+ influx and formulated from data that was recorded during beta-adrenergic stimulation of the myocytes. Ca2+ influx and its competition with non-selective monovalent cation permeation were also incorporated into channel permeation in the model. The constructed model could closely reproduce the experimental Ba2+ and Ca2+ current results under basal condition where no beta-stimulation was added after a slight reduction of the development of fast voltage-dependent inactivation with depolarization. The model also predicted that under beta-adrenergic stimulation voltage-dependent inactivation is lost and calcium-dependent inactivation largely compensates it. The developed model thus will be useful to estimate the respective roles of VDI and CDI of L-type Ca2+ channels in various physiological and pathological conditions of the heart which would otherwise be difficult to show experimentally.
L型Ca2+电流的失活由电压依赖性和钙依赖性机制组成。这些过程的相对贡献仍存在争议，而电压依赖性失活可能会受到其他生理过程进一步调节的观点一直被忽视。本研究旨在根据最近的详细实验数据，对心室肌细胞中该电流失活的生理调节进行建模。该实验数据通过用Mg2+替代细胞外Ca2+来分离总失活和电压依赖性失活（VDI），并在无内向电流流动的情况下，通过流经通道的外向K+电流监测L型Ca2+通道行为。钙依赖性失活（CDI）基于Ca2+内流，并根据心肌细胞β-肾上腺素能刺激期间记录的数据来制定。Ca2+内流及其与非选择性单价阳离子通透的竞争也被纳入模型中的通道通透过程。构建的模型在基础条件下（即去极化后轻微降低快速电压依赖性失活的发展且未添加β-刺激时），能够紧密重现实验性Ba2+和Ca2+电流结果。该模型还预测，在β-肾上腺素能刺激下，电压依赖性失活消失，钙依赖性失活在很大程度上对其进行补偿。因此，所开发的模型将有助于评估L型Ca2+通道的VDI和CDI在心脏各种生理和病理状况下各自的作用，否则这些作用很难通过实验来显示。
