A detailed, conductance-based computer model of intrinsic sensory neurons of the gastrointestinal tract
A detailed, conductance-based computer model of intrinsic sensory neurons of the gastrointestinal tract
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DOI：
10.1152/ajpgi.00228.2013
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发表时间：
2014-09-01
影响因子：
4.5
通讯作者：
Thomas, Evan A.
中科院分区：
文献类型：
--
作者：
Chambers, Jordan D.;Bornstein, Joel C.;Thomas, Evan A.
肠道神经系统的内源性感觉神经元(ISN)对肌肉张力、肌肉长度、粘膜变形和管腔中的化学成分等刺激做出反应。ISNS形成循环网络，可能驱动许多肠道运动模式和反射。ISN表达大量的电压和钙门控离子通道，其中一些可被炎症或重复的生理刺激所改变，但iSN中不同离子电流之间的相互作用如何在肠道中产生正常和病理行为仍不清楚。我们构建了包括电压门控钠钾通道、N型钙通道、大电导钙依赖钾(BK)通道、钙依赖非特异性阳离子通道(NSCA)、中等电导钙依赖钾(IK)通道、超极化激活阳离子(I-h)通道和内钙动力学的iSNS模型。该模型是基于文献和我们的电生理学研究的数据。该模型再现了对短或长去极化电流脉冲的反应，以及对长超极化电流脉冲的反应。敏感性分析表明，I-h、Ik、NSCA和BK对延长去极化过程中观察到的动作电位数目的影响最大。该模型还预测了i-h激活电压的变化对激发度的影响较大，而i-h激活时间常数的变化对激发度的影响较小。我们的模型确定了不同标志性电流之间的相互作用如何影响iSNS的兴奋性，并强调了i-h在疾病引起的肠神经可塑性中的重要作用。
Intrinsic sensory neurons (ISNs) of the enteric nervous system respond to stimuli such as muscle tension, muscle length, distortion of the mucosa, and the chemical content in the lumen. ISNs form recurrent networks that probably drive many intestinal motor patterns and reflexes. ISNs express a large number of voltage-and calcium-gated ion channels, some of which are modified by inflammation or repeated physiological stimuli, but how interactions between different ionic currents in ISNs produce both normal and pathological behaviors in the intestine remains unclear. We constructed a model of ISNs including voltage-gated sodium and potassium channels, N-type calcium channels, big conductance calcium-dependent potassium (BK) channels, calcium-dependent nonspecific cation channels (NSCa), intermediate conductance calcium-dependent potassium (IK) channels, hyperpolarization-activated cation (I-h) channels, and internal calcium dynamics. The model was based on data from the literature and our electrophysiological studies. The model reproduced responses to short or long depolarizing current pulses and responses to long hyperpolarizing current pulses. Sensitivity analysis showed that I-h, IK, NSCa, and BK have the largest influence on the number of action potentials observed during prolonged depolarizations. The model also predicts that changes to the voltage of activation for I-h have a large influence on excitability, but changes to the time constant of activation for I-h have a minor effect. Our model identifies how interactions between different iconic currents influence the excitability of ISNs and highlights an important role for I-h in enteric neuroplasticity resulting from disease.