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首页> 外文期刊>Journal of Computational Neuroscience >A computational model of large conductance voltage and calcium activated potassium channels: implications for calcium dynamics and electrophysiology in detrusor smooth muscle cells
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A computational model of large conductance voltage and calcium activated potassium channels: implications for calcium dynamics and electrophysiology in detrusor smooth muscle cells

机译：大电导电压和钙活化钾通道的计算模型：对逼尿肌平滑肌细胞钙动力学和电生理学的影响

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摘要

The large conductance voltage and calcium activated potassium (BK) channels play a crucial role in regulating the excitability of detrusor smooth muscle, which lines the wall of the urinary bladder. These channels have been widely characterized in terms of their molecular structure, pharmacology and electrophysiology. They control the repolarising and hyperpolarising phases of the action potential, thereby regulating the firing frequency and contraction profiles of the smooth muscle. Several groups have reported varied profiles of BK currents and I-V curves under similar experimental conditions. However, no single computational model has been able to reconcile these apparent discrepancies. In view of the channels' physiological importance, it is imperative to understand their mechanistic underpinnings so that a realistic model can be created. This paper presents a computational model of the BK channel, based on the Hodgkin-Huxley formalism, constructed by utilising three activation processes membrane potential, calcium inflow from voltage-gated calcium channels on the membrane and calcium released from the ryanodine receptors present on the sarcoplasmic reticulum. In our model, we attribute the discrepant profiles to the underlying cytosolic calcium received by the channel during its activation. The model enables us to make heuristic predictions regarding the nature of the sub-membrane calcium dynamics underlying the BK channel's activation. We have employed the model to reproduce various physiological characteristics of the channel and found the simulated responses to be in accordance with the experimental findings. Additionally, we have used the model to investigate the role of this channel in electrophysiological signals, such as the action potential and spontaneous transient hyperpolarisations. Furthermore, the clinical effects of BK channel openers, mallotoxin and NS19504, were simulated for the detrusor smooth muscle cells. Our findings support the proposed application of these drugs for amelioration of the condition of overactive bladder. We thus propose a physiologically realistic BK channel model which can be integrated with other biophysical mechanisms such as ion channels, pumps and exchangers to further elucidate its micro-domain interaction with the intracellular calcium environment.
机译：大电导电压和钙活化钾（BK）通道在调节尿造器平滑肌的兴奋方面发挥着至关重要的作用，该乳糊状肌的兴奋性地围绕膀胱壁排列。这些频道已广泛表征在其分子结构，药理学和电生理学方面。它们控制动作电位的复发和超极化阶段，从而调节平滑肌的烧制频率和收缩谱。几组在类似的实验条件下报道了BK电流和I-V曲线的各种曲线。但是，没有单一计算模型能够协调这些明显的差异。鉴于渠道的生理重要性，必须了解他们的机械支撑，以便可以创建一个现实模型。本文介绍了通过利用三种激活过程膜电位构成的霍奇金豪利的形式主义的BK通道的计算模型，从膜上释放的膜和钙释放的膜上的电压门控钙通道的钙流入网状物。在我们的模型中，在激活期间，我们将差异曲线归因于通道接收的底层细胞溶质钙。该模型使我们能够对BK信道激活的亚膜钙动力学的性质进行启发式预测。我们使用该模型来繁殖渠道的各种生理特征，并发现符合实验结果的模拟反应。此外，我们使用该模型来研究该信道在电生理信号中的作用，例如动作电位和自发瞬态超极化。此外，模拟了BK通道开启器，马来毒毒素和NS19504的临床影响，用于逼尿肌平滑肌细胞。我们的调查结果支持拟议的这些药物适用于过度活跃膀胱的状况。因此，我们提出了一种生理学上现实的BK信道模型，其可以与其他生物物理机制集成，例如离子通道，泵和交换器，以进一步阐明其与细胞内钙环境的微观域相互作用。

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