Ion Channel Markov Modeling And Analysis An Evolutionary Computation Method

Electrical behaviors in live cells, which based on the Physical activity of ion channels, are one of essential characters of life. Many important physiological processes are correlate with ion channel, such as cell excitability, cell volume, stable intracellular environment, the generation and conduction of nerve signals, cell division, reproductive development, muscle movement, hormone and neurotransmitter secretion, etc. Therefore both in theory and practice, it’s greatly significant to find the mechanism of ion channel in cell activities.BK(Large-conductance calcium-activated potassium) channel is one type of ion channels, which is widely expressed in excitable and non-excitable cells, and functions in many important physiological process, such as:the formation of action potential and muscle movement, etc. Its calcium sensitivity and (31subunit is critical to the transmit of neural signal and vascular tone, with a high research value and significance.In the methods of ion channel working mechanism study, ion channel Markov model is a mathematical model which can reflect dynamic relationship of transitions between the states of channel in specific physiological and environmental conditions. The significance of building the Markov model is to characterize the working mechanism of the ion channel quantitatively, to explain the structure and physiological function of ion channel protein and to reveal the pathogenic mechanism of ion channel-related diseases. However, during Markov modeling process, there are several difficulties:too complex model structure, too many model parameters, too many data used in modeling and so on, which can not be easily solved by traditional methods. Except Markov modeling, in BK calcium sensitivity measurement and β1subunit function analysis, complex inverse problem solving is involved, which can not be solved by existed method.Evolutionary computation, which based on natural evolution, specializes in solving global optimization problems with the probabilistic search technology. Its search process does not depend on the initial value, gradient information or other auxiliary knowledge. It’s adptive for the kind of issue, therefore it’s usful in ion channel modeling and inverse problem solving. In this dissertation, electrophysiological techniques combined with computer simulation method are used. First, we built Markov models for many ion channels using evolutionary computation method. Then the calcium sensitivity and β1functions in BK channels are analyzed quantitatively:First, a software CeL was developed, based on an evolutionary computation method we designed, PSO-GSS. To make the modeling process more efficient and faster, we proposed a method of estimating the initial values of the model parameters from macroscopic currents, which can be applied in parameters optimization of each model, and a better result can be gotten. Compare with the software with similar functions,CeL was much better in the modeling performance and have reached the international advanced level. Additionally, using CeL, we analyzed a mass of electrophysiological data from experiments and built many Markov models of different channels:BK, Kv, Ca, Nay and so on.Second, by means of laser flash photolysis techniques, several unusual properties of BK currents were found:biphasic activation and voltage-dependent constant Rf. Using ES and BK flash current as a sensor, we accurately calculated the intracellular local calcium concentration change process firstly in the world. Additionally, a method was proposed to estimate the binding rate constant of [Ca2+] in the article and the [Ca2+] binding rate constant of four BK mutant were determined. Considering Ca2+’s function of second messenger in BK channel, this work was greatly significant for the study of the mechanism of generation and conduction of nerve signals.Finally, BK(mSloa) and BK(mSloα+β1) currents were analyzed, and using which the relative50-states BK models were built. The built model was the first one in the world. Using the built50-states BK model, we successfully built the SM cell model and simulate their action potential. This study concluded that (31subunit enhanced hyperpolarization of cells and reduced intracellular calcium concentration, which lead to the relaxation of arteries. The work had laid a basis for underlying the vasoregulation mechanism. Additionally, because the changes in intracellular Ca2+were consistent to the changes in diameters of arteries, the β1subunit gene should be a candidate genetic locus for human hypertension. In summary, our study demonstrates the the calcium sensitivities and the function of β1subunit in BK channels and their mutants, which can be future used in the mechanism research of vasoregulation and nerve activities. Meanwhile, as an innovation research way, CeL and its derivative methods expand the technique of biophysical study and greatly improves the efficiency of researches.