Mathematical-Computational Model for Simulating Kinetic and Steady-State Voltage-Dependent Gating of Gap Junctions
| Author | Affiliation |
|---|---|
Verselis, Vytautas Kazimieras | Albert Einstein College of Medicine, New York, USA |
| Date |
|---|
2022-07-16 |
Gap junction channels can gate robustly in response to transjunctional voltage, Vj, the voltage difference between two coupled cells. Vj gating of gap junction channels could play a physiological role, particularly in excitable cells, which can generate large Vj transients during the propagation of action potentials. To assess these properties, we developed a mathematical-computational model of gap junction channel Vj gating that takes into account Vj distribution and contingent gating of two series hemichannels. First, to validate our model, we fitted various data sets obtained from electrophysiological recordings in cell cultures expressing cardiac connexins Cx43 and Cx45, using global optimization methods. The results showed that the model is capable of describing both steady-state and kinetic properties of homotypic and heterotypic gap junction channels composed of these connexins. To demonstrate the applicability of the model, we show its ability to adequately describe complex behaviors of gap junction channels, which connects the networks of excitable cells. For example, our electrophysiological and modeling data show that Vj transients, which develop during the spread of cardiac action potentials, are capable to significantly reduce junctional conductance of heterotypic Cx43/Cx45 GJ channels. In addition, the model can reproduce strong coupling asymmetry in cells connected through Cx43/Cx45 channels, which was observed in voltage and current clamp experiments. Moreover, we address models applicability for evaluation of single channel characteristics, such as an open state probability and average dwelling times, from macroscopic recordings of junctional conductance. This could help to reduce the amount of technically difficult experiments at a single-channel level. Overall, this model can serve as a tool for the studying of GJ channel gating and its effects on the electrically coupled cells..