BKs和BKi通道在大鼠嗜铬细胞动作电位中的作用

发布时间：2018-04-09 15:45

本文选题：BK通道　切入点：H-H模型　出处：《华中科技大学》2008年博士论文

【摘要】： BK通道是一种能同时响应细胞膜电压和胞内钙浓度变化的钾离子通道。它广泛地存在于除心脏肌细胞外的可兴奋细胞和不可兴奋细胞中,对调节细胞膜电位起到重要作用。然而,由于它复杂的动力学机制,传统的Hodgkin-Huxley(H-H)模型不能很好地表述其动力学特征,进而也就不能描述其在动作电位中的功能。本课题中,我们提出用MWC变构动力学模型来描述BK通道,取代H-H模型中简单的表达式的方法,然后用它模拟大鼠嗜铬细胞中BK通道对动作电位的贡献。本文以BK通道为研究对象,针对实验数据进行了详尽分析,对通道的激活、去激活、失活、恢复等变构过程给予了说明,提出相应的动力学模型,并给出了确定模型参数的方法。在对BKi去激活实验数据的尾电流进行分析的时候,针对其出现的整流现象,我们将传统的离子电导的计算方法进行了剖析,进而对H-H模型中有关离子电导的计算表达式做了相应的调整。在引入蛋白质变构模型理论的基础上,我们从生物物理过程和化学动力学的角度,对离子通道的状态改变有了更为进一步的认识。我们将变构模型的状态之间的转换与马尔科夫过程联系起来,并应用微分方程的观点提出了对模型状态的分布概率求解的方法。为此,我们用了几年的时间编写了一套模型仿真程序CeL。该程序应用变步长的Runge-Kutta算法,对状态模型构成的微分方程组进行时间上的积分求解,实现了对离子通道电流的模拟。根据总的跨膜电流与膜电容和膜电压之间的关系,在对各离子通道建立模型的基础之上,我们又进而实现了对动作电位的模拟。通过比较实验数据和模拟结果,我们首次证明:BK通道对动作电位的复极化、超极化,以及后超极化过程具有重要的调节作用;有失活的BK(BKi)通道有利于动作电位的连续发放;无失活的BK(BKs)通道阻碍动作电位的连续发放;在动作电位发放期间,BKi的电流由小逐渐增大然后减小至一个稳定的水平,而BKs的电流则持续地增大;当没有外钙时,BKs和BKi细胞都只能发放一个动作电位。我们发现促进动作电位连续发放的BK(BKi)通道的关键点不在于beta2亚基诱发通道失活,而是在于beta2亚基使通道变得更容易激活。由于我们各通道的动力学模型很容易获得并且远比表达式灵活、精确,因此,新方法不仅比H-H模型更精确和更方便,而且可以被用来研究更复杂的离子通道。不仅如此,该方法对研究细胞中的分泌过程也有广泛地应用。
[Abstract]:BK channel is a potassium channel which can simultaneously respond to the change of cell membrane voltage and intracellular calcium concentration.It widely exists in excitable and unexcitable cells except cardiac muscle cells and plays an important role in regulating cell membrane potential.However, because of its complex dynamic mechanism, the traditional Hodgkin-Huxley H-HG model can not describe its dynamic characteristics well, and thus its function in action potential can not be described.In this paper, we propose a method to describe BK channel by using MWC model to replace the simple expression in H-H model, and then simulate the contribution of BK channel to action potential in rat chromaffin cells.In this paper, the BK channel is taken as the research object, the experimental data are analyzed in detail, the process of channel activation, deactivation, inactivation and restoration is explained, and the corresponding dynamic model is proposed.The method of determining the model parameters is also given.When analyzing the tail current of BKi deactivation experiment data, we analyze the traditional calculation method of ionic conductance in view of its rectifying phenomenon.Furthermore, the calculation expressions of ion conductance in H-H model are adjusted accordingly.On the basis of introducing the theory of protein metamorphic model, we have a further understanding of the state change of ion channel from the point of view of biophysical process and chemical kinetics.The transformation between the states of the model is connected with the Markov process, and the method of solving the distribution probability of the model state is presented by applying the viewpoint of differential equation.To this end, we have written a model simulation program CeLL for several years.In this program, a variable step size Runge-Kutta algorithm is used to solve the time integral of the differential equations composed of the state model, and the simulation of the ion channel current is realized.According to the relationship between the total transmembrane current and the membrane capacitance and the membrane voltage, on the basis of the model of each ion channel, we have realized the simulation of the action potential.By comparing the experimental data with the simulation results, we prove for the first time that the repolarization, hyperpolarization and post-hyperpolarization of the action potential are regulated by the BK channel, and that the inactivated BKN BKiI channel is beneficial to the continuous release of the action potential.The non-inactivated BKN BKs channel hinders the continuous release of the action potential, and the current of BKi increases gradually from a small to a stable level during the release of the action potential, while the current of BKs increases continuously.When there is no extracellular calcium, both BKs and BKi cells can emit only one action potential.We found that the key point to promote the continuous release of action potential is not the inactivation of the beta2 subunit induced channel, but the fact that the beta2 subunit makes the channel more easily activated.Because the kinetic models of our channels are easy to obtain and far more flexible and accurate than the expressions, the new method is not only more accurate and convenient than the H-H model, but also can be used to study more complex ion channels.Not only that, this method is also widely used to study the secretion process in cells.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2008
【分类号】：R33

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