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.

中文翻译：

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大电导电压和钙激活钾通道的计算模型：对逼尿肌平滑肌细胞中钙动力学和电生理的影响。

大的电导电压和钙激活的钾（BK）通道在调节逼尿肌平滑肌的兴奋性中起着至关重要的作用，逼尿肌平滑肌排在膀胱壁上。这些通道的分子结构，药理学和电生理学已被广泛表征。它们控制动作电位的重新极化和超极化阶段，从而调节平滑肌的放电频率和收缩曲线。几个小组报告了在相似的实验条件下BK电流和IV曲线的变化曲线。但是，没有单一的计算模型能够解决这些明显的差异。考虑到通道的生理重要性，必须了解它们的机械基础，以便可以创建逼真的模型。本文介绍了一种基于Hodgkin-Huxley形式主义的BK通道的计算模型，该模型通过利用三个激活过程构建—膜电位，膜上电压门控钙通道的钙流入以及从存在于脑中的ryanodine受体释放的钙。肌质网。在我们的模型中，我们将差异特征归因于通道在激活过程中所接收的潜在胞质钙。该模型使我们能够根据BK通道激活的亚膜钙动力学性质进行启发式预测。我们已经使用该模型来重现通道的各种生理特征，并发现模拟响应与实验结果一致。另外，我们已经使用该模型研究了该通道在电生理信号中的作用，例如动作电位和自发性瞬时超极化。此外，模拟了逼尿肌平滑肌细胞的BK通道开放剂，Mallotoxin和NS19504的临床效果。我们的发现支持这些药物用于改善膀胱过度活动症的建议应用。因此，我们提出了一种生理上可行的BK通道模型，该模型可与其他生物物理机制（例如离子通道，泵和交换器）集成在一起，以进一步阐明其与细胞内钙环境的微域相互作用。对逼尿肌平滑肌细胞模拟了Mallotoxin和NS19504。我们的发现支持这些药物用于改善膀胱过度活动症的建议应用。因此，我们提出了一种生理上可行的BK通道模型，该模型可以与其他生物物理机制（例如离子通道，泵和交换器）集成在一起，以进一步阐明其与细胞内钙环境的微域相互作用。对逼尿肌平滑肌细胞模拟了Mallotoxin和NS19504。我们的发现支持这些药物用于改善膀胱过度活动症的建议应用。因此，我们提出了一种生理上可行的BK通道模型，该模型可以与其他生物物理机制（例如离子通道，泵和交换器）集成在一起，以进一步阐明其与细胞内钙环境的微域相互作用。