Department of Computational Biology, School of Computer Science and Communication, Royal Institute of Technology, Stockholm, Sweden.
Biophys J. 2011 Oct 19;101(8):1871-9. doi: 10.1016/j.bpj.2011.08.055.
In diseases of the brain, the distribution and properties of ion channels display deviations from healthy control subjects. We studied three cases of ion channel alteration related to epileptogenesis. The first case of ion channel alteration represents an enhanced sodium current, the second case addresses the downregulation of the transient potassium current K(A), and the third case relates to kinetic properties of K(A) in a patient with temporal lobe epilepsy. Using computational modeling and optimization, we aimed at reversing the pathological characteristics and restoring normal neural function by altering ion channel properties. We identified two key aspects of neural dysfunction in epileptogenesis: an enhanced response to synaptic input in general and to highly synchronized synaptic input in particular. In previous studies, we showed that the potassium channel K(A) played a major role in neural responses to highly synchronized input. It was therefore selected as the target upon which modulators would act. In biophysical simulations, five experimentally characterized endogenous modulations on the K(A) channel were included. Relative concentrations of these modulators were controlled by a numerical optimizer that compared model output to predefined neural output, which represented a normal physiological response. Several solutions that restored the neuron function were found. In particular, distinct subtype compositions of the auxiliary proteins Kv channel-interacting proteins 1 and dipeptidyl aminopeptidase-like protein 6 were able to restore changes imposed by the enhanced sodium conductance or suppressed K(A) conductance. Moreover, particular combinations of protein kinese C, calmodulin-dependent protein kinase II, and arachidonic acid were also able to restore these changes as well as the channel pathology found in a patient with temporal lobe epilepsy. The solutions were further analyzed for sensitivity and robustness. We suggest that the optimization procedure can be used not only for neurons, but also for other organs with excitable cells, such as the heart and pancreas where channelopathies are found.
在脑部疾病中，离子通道的分布和性质表现出与健康对照不同的特征。我们研究了三种与癫痫发生相关的离子通道改变的病例。第一种离子通道改变的病例表现为钠离子电流增强，第二种病例涉及瞬时钾电流 K(A) 的下调，第三种病例与颞叶癫痫患者的 K(A)动力学特性有关。我们使用计算建模和优化，旨在通过改变离子通道特性来逆转病理特征并恢复正常神经功能。我们确定了癫痫发生中神经功能障碍的两个关键方面：对突触输入的一般反应增强，特别是对高度同步化的突触输入的反应增强。在之前的研究中，我们表明钾通道 K(A)在神经对高度同步化输入的反应中起着主要作用。因此，它被选为调节剂作用的靶点。在生物物理模拟中，包括了五个对 K(A)通道有特征性的内源性调节作用。这些调节剂的相对浓度由一个数值优化器控制，该优化器将模型输出与代表正常生理反应的预定义神经输出进行比较。找到了几种恢复神经元功能的解决方案。特别是，辅助蛋白 Kv 通道相互作用蛋白 1 和二肽基氨肽酶样蛋白 6 的不同亚型组成能够恢复增强的钠电导或抑制的 K(A)电导所施加的变化。此外，蛋白激酶 C、钙调蛋白依赖性蛋白激酶 II 和花生四烯酸的特定组合也能够恢复这些变化以及在颞叶癫痫患者中发现的通道病理。进一步对解决方案进行了敏感性和稳健性分析。我们建议，该优化程序不仅可用于神经元，还可用于其他具有可兴奋细胞的器官，如心脏和胰腺，这些器官中也存在通道病。
