Phasic ion channel blockade. A kinetic model and parameter estimation procedure.
Phasic ion channel blockade. A kinetic model and parameter estimation procedure.
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DOI：
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发表时间：
1985-10
影响因子：
3.6
通讯作者：
C. Starmer;A. Grant
中科院分区：
文献类型：
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作者：
C. Starmer;A. Grant
对于可兴奋膜，使用和频率依赖表示药物在重复刺激下逐渐并入门控离子通道。与受体对配体的访问在时间上是连续的相反，我们定义了守卫受体，如门控离子通道，作为受体对配体池的访问是短暂的，由通道门控过程控制。在重复刺激过程中，配体结合通道（离子通道阻断）的比例遵循指数时间过程，由刺激间隔、通道门控过程、药物浓度以及结合过程特征的正向和反向速率系数决定。基于配体-受体结合的一阶模型，我们推导了在重复相位刺激条件下通过单一扩散路径对离子通道阻断的表征。扩展到多个扩散路径和多种药物导致一个更复杂的方案，但这些概括是直接的。对于一种扩散路径，我们导出了受保护受体通道阻断的稳态水平作为刺激速率的函数，并开发了适合于表征离子通道阻断剂（如局部麻醉剂和抗心律失常药物）的数据分析策略。研究表明，随着受体进入时间的增加，受保护受体的瞬态和稳态性质与标准连续进入配体-受体模型等效。所提出的分析工具简化了许多离子通道阻滞剂功能特性的定量描述，似乎对周期性可及受体的表征具有普遍适用性。
For excitable membranes, use and frequency dependence represent a progressive incorporation of drug into gated ion channels with repetitive stimulation. In contrast to receptors where access to ligand is continuous in time, we define guarded receptors, such as gated ion channels, as receptors whose access to the ligand pool is transient and controlled by the channel-gating process. During repetitive stimulation, the fraction of ligand-bound channels (ion channel blockade) follows an exponential time course, determined by the interstimulus interval, channel-gating processes, drug concentration, and the forward and reverse rate coefficients characteristic of the binding process. Based on a first order model of ligand-receptor binding, we derive a characterization of ion channel blockade via a single diffusion path under conditions of repetitive phasic stimulation. Extension to multiple diffusion paths and multiple drugs leads to a more complex scheme, but these generalizations are straightforward. For the case of one diffusion path, we derive the steady state level of channel blockade for guarded receptors as a function of stimulus rate and develop a data analysis strategy suitable for characterizing ion channel-blocking agents such as local anesthetics and antiarrhythmic drugs. We show that as receptor access time increases, the transient and steady state properties of guarded receptors become equivalent to those derived from the standard continuous access ligand-receptor model. The analysis tools presented simplify the quantitative description of the functional properties of many ion channel blockers and appear to have general applicability to characterization of periodically accessible receptors.