Here, we have provided a qualitative theoretical description about how the action potential generation and its associated intrinsic properties such as ionic current, spiking frequency, action potential duration, gating dynamics, etc. are affected due to site selective ion channel blockers, by suitably adapting Gillespie’s stochastic simulation technique to an extended Hodgkin–Huxley Markov model, representing a very basic type of neuron. Considering different types and degrees of blocking potency of channel blockers to channel proteins, we have found that the nature of action potential termination process and corresponding ionic current profiles are very distinct from each other. With the increasing blocking affinity, the frequency of action potential spiking falls off exponentially in presence of sodium channel only blockers and dual type blockers having more sodium binding potency than potassium blockers, whereas in contrast, for potassium channel only blockers, dual type blockers having equal or higher potassium blocking affinity with respect to sodium blocking, the spiking frequency initially is enhanced followed by a gradual decrease due to the competition between channel number fluctuation and overall sodium and potassium conductances. Sodium channel blockers tend to shorten the action potential duration while the potassium channel blockers broaden it. The channel gating dynamics are also found to be changed drastically for different types of blockers. The final quiescent state arrival time and the quiescent state membrane voltage profiles show distinct features for different types of channel blockers with different applied external stimulus. Finally, we showed how consistent our results are with the existing literature of experimentally observed channel blocking effects in diverse systems and compared the similarities, dissimilarities and advantages of our model with an existing theoretical drug binding model with Langevin description. Our approach provides a qualitative pathway to investigate the effects of many other types of blocking mechanisms such as closed state, inactivated state blocking with desired level of structural and functional details.

中文翻译：

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位点选择性离子通道阻滞剂导致动作电位终止

在这里，我们提供了关于动作电位产生及其相关固有特性（如离子电流、尖峰频率、动作电位持续时间、门控动力学等）如何受到位点选择性离子通道阻滞剂影响的定性理论描述，通过适当地调整Gillespie 对扩展的 Hodgkin-Huxley Markov 模型的随机模拟技术，代表了一种非常基本的神经元类型。考虑到通道阻滞剂对通道蛋白的不同类型和不同程度的阻断效力，我们发现动作电位终止过程的性质和相应的离子电流分布非常不同。随着阻断亲和力的增加，在仅钠通道阻滞剂和具有比钾阻滞剂更强的钠结合效力的双型阻滞剂存在下，动作电位尖峰频率呈指数下降，而相比之下，对于仅钾通道阻滞剂，具有相同或更高钾阻滞亲和力的双型阻滞剂与关于钠阻断，由于通道数波动与总钠和钾电导之间的竞争，尖峰频率最初会增强，然后逐渐降低。钠通道阻滞剂倾向于缩短动作电位持续时间，而钾通道阻滞剂则延长它。还发现对于不同类型的阻滞剂，通道门控动态发生了巨大变化。最终静止状态到达时间和静止状态膜电压曲线显示不同类型的通道阻滞剂与不同施加的外部刺激的不同特征。最后，我们展示了我们的结果与在不同系统中实验观察到的通道阻断效应的现有文献的一致性，并将我们的模型与现有的理论药物结合模型与 Langevin 描述的相似性、不同点和优势进行了比较。我们的方法提供了一种定性途径来研究许多其他类型的阻塞机制的影响，例如关闭状态、具有所需结构和功能细节水平的失活状态阻塞。我们展示了我们的结果与在不同系统中实验观察到的通道阻断效应的现有文献的一致性，并将我们的模型与现有的理论药物结合模型与 Langevin 描述的相似性、不同点和优势进行了比较。我们的方法提供了一种定性途径来研究许多其他类型的阻塞机制的影响，例如关闭状态、具有所需结构和功能细节水平的失活状态阻塞。我们展示了我们的结果与在不同系统中实验观察到的通道阻断效应的现有文献的一致性，并将我们的模型与现有的理论药物结合模型与 Langevin 描述的相似性、不同点和优势进行了比较。我们的方法提供了一种定性途径来研究许多其他类型的阻塞机制的影响，例如关闭状态、具有所需结构和功能细节水平的失活状态阻塞。