Department of Medicine, Mayo Clinic Rochester, MN, USA.
Richard D. Berlin Center for Cell Analysis and Modeling, University of Connecticut Health Center Farmington, CT, USA.
Front Neurosci. 2015 Jan 21;8:453. doi: 10.3389/fnins.2014.00453. eCollection 2014.
A suite of models was developed to study the role of inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in spinocerebellar ataxias (SCAs). Several SCAs are linked to reduced abundance of IP3R1 or to supranormal sensitivity of the receptor to activation by its ligand inositol 1,4,5-trisphosphate (IP3). Detailed multidimensional models have been created to simulate biochemical calcium signaling and membrane electrophysiology in cerebellar Purkinje neurons. In these models, IP3R1-mediated calcium release is allowed to interact with ion channel response on the cell membrane. Experimental findings in mice and clinical observations in humans provide data input for the models. The SCA modeling suite helps interpret experimental results and provides suggestions to guide experiments. The models predict IP3R1 supersensitivity in SCA1 and compensatory mechanisms in SCA1, SCA2, and SCA3. Simulations explain the impact of calcium buffer proteins. Results show that IP3R1-mediated calcium release activates voltage-gated calcium-activated potassium channels in the plasma membrane. The SCA modeling suite unifies observations from experiments in a number of SCAs. The cadre of simulations demonstrates the central role of IP3R1.
开发了一套模型来研究肌醇 1,4,5-三磷酸受体 1（IP3R1）在脊髓小脑共济失调（SCA）中的作用。几种 SCA 与 IP3R1 丰度降低或受体对其配体肌醇 1,4,5-三磷酸（IP3）激活的超敏性有关。已经创建了详细的多维模型来模拟小脑浦肯野神经元中的生化钙信号和膜电生理学。在这些模型中，允许 IP3R1 介导的钙释放与细胞膜上的离子通道反应相互作用。来自小鼠的实验发现和人类的临床观察为模型提供了数据输入。SCA 建模套件有助于解释实验结果并提供指导实验的建议。该模型预测 SCA1 中的 IP3R1 超敏性和 SCA1、SCA2 和 SCA3 中的代偿机制。模拟解释了钙缓冲蛋白的影响。结果表明，IP3R1 介导的钙释放激活质膜上的电压门控钙激活钾通道。SCA 建模套件将多种 SCA 中的实验观察结果统一起来。这一系列模拟表明了 IP3R1 的核心作用。
