Analysis of Electrical Cell-to-Cell Communication Using the Aggregate of Model Cells

Abstract

When muscle cells are excited electrically, the membrane potentials of entire cells change simultaneously from a resting potential to an action potential. For smooth muscles, depolarization caused by pacemaker cells spreads to neighboring cells via gap junctions.1) Because Ca2+ or K+ flows through gap junctions between neighboring cells, a local circulating current is generated between the two cells. A change in membrane potential from resting to action potential therefore propagates through the muscle tissue. The same propagation mechanism is assumed to occur in cardiac muscle tissue. The propagation of electric signals among neighboring cells within the cell aggregate has been proposed based on the local circulating current. Voltage-sensitive dyes have been used to monitor partial membrane potentials of single living cells, because it is difficult to simultaneously measure the membrane potentials in multiple places. In addition, because it is almost impossible to simultaneously monitor the changes in the membrane potentials of multiple cells in a given tissue, a detailed propagation mechanism of the action potential among multiple living cells has yet to been clarified yet. On the other hand, K+ and Na+ channels play important roles in nerve conduction. We have proposed a new propagation mechanism for action potential in nerve conduction using model systems composed of multiple liquid-membrane cells.2) Ligand-gated Na+ channel in a synapse behaves as electric power sources that propagate changes in membrane potential toward the synaptic terminal, and voltage-gated Na+ channels on the nerve axon serve as supporting electric power sources to assist with directional propagation of the action potential. In addition, action potential appears to be caused by an external electrical stimulus. The circulating current generated in the model-cell system partially provokes a change in membrane potential from a resting potential to an action potential, and the action potential propagated to neighboring cell systems sequentially. In this study, signal transmission among multiple cell bodies was elucidated by constructing a model-cell system composed of multiple liquid-membrane cells that mimic the function of K+ and Na+ channels. Signal transmission among model-cell units caused by activation of a given model-cell unit or an external electric stimulus was investigated by analyzing the relationship among the respective membrane potentials and the currents flowing through the respective liquid-membrane cells. To imitate tissues such as muscles, cardiac muscles, and brains, liquid-membrane cells mimicking the function of K+ and Na+ channels were made. Action-potential propagation within the cell aggregate model constructed by multiple model cells was investigated. When the action potential was generated at a given cell, the cell behaved as an electric power source and a current partly flowed through neighboring model cells. Influx and efflux currents caused hyperpolarization and depolarization, respectively, on the surface of neighboring model cells, and the action potential was generated at the depolarized domain of the neighboring model cells. The action potential then spread over all the model cells one after another. When an external electric stimulus was applied to the cell aggregate model system, most cells were simultaneously excited as if they were synchronized. By measuring the electric currents and membrane potentials of respective cells, a mechanism for action-potential propagation among multiple cells has been suggested. The initial depolarized cell behaved as an additional electric power source, and the current locally flowed the outside. According to Kirchhoff’s law, the sum of electric currents flowing through each cell is zero, and the inward and outward currents are equivalent. Considering the relationship between the membrane current and the membrane potential on the channel function of the plasma membrane, an inward current causes hyperpolarization and an outward current provokes depolarization. Because the depolarization at one part of a cell activates neighboring voltage-gated Na+ channels in sequence, the membrane potential of the whole cell is then depolarized. The excited cell behaves as an additional electric power source and propagates the action potential to neighboring cells. It is clear that action-potential propagation to distant cells is delayed by resistances according to the distance between the excited cell and the objective non-excited cell. Thus, external electric stimuli can induce action-potential propagation more smoothly.References1) M.J. Berridge, J. Physiol., 2008, 586, 5047-5061.2) O. Shirai, Y. Kitazumi, and K. Kano, Electroanalysis, 2017, 29, 2656-2664.