Gap junction (GJ) channels enable electrical impulse propagation in cardiac tissue, synchronization of neuronal networks and coordination of insulin secretion in pancreatic beta cells. In addition, direct coupling through open GJ channels enables the transfer of metabolites and small signalling molecules, which is important for such physiological and pathological processes as formation of tumours and response to inflammation. For these reasons, GJs are increasingly chosen as a possible target for the creation of new drugs and therapeutic methods.
The measurement of junctional conductance is an important research tool which allows for evaluation of the function of GJ channels, formed of wild-type or mutant connexin (Cx) protein, under physiological and various pathological conditions. In order to evaluate biophysical properties of GJ channels, mathematical/computational models are often applied for interpretation of data obtained from electrophysiological recordings.
Thus far, the created models have only allowed for an adequate description of macroscopic conductance. However, in order to evaluate such important biophysical characteristics as voltage gating polarity or open channel probability, it is necessary to measure the conductance at a single-channel level. Based on our previous research, we propose to develop a mathematical/computational model, which would allow for simulation of probabilistic behaviour of unitary GJ channels. To evaluate the validity of the model, we will fit it to electrophysiological data obtained from cell cultures transfected with various types of Cx protein. Model development and parameter estimation will be performed using global optimization and machine learning methods.
The developed model will serve as a valuable research tool, because it will allow one to combine electrophysiological data recorded at macroscopic and single-channel level. In addition, it will be a valuable for simulation of cell networks, coupled through GJ channels.
Project funding:
KTU Research and Innovation Fund
Project results:
During the project, we developed the methodology which allows to extract information about of gap junction channel gating using electrophysiological data recorded at a single-channel level. This methodology is based on rapid equilibrium assumption-based approximation of our previously published four-state model and maximum likelihood estimation-based analysis.
In addition, we developed mathematical models, which could explain Mg2+-mediated regulation of Cx36 GJ channels. Our combined mathematical / computational modelling and electrophysiological data revealed a feasible mechanism for this regulation, which can be divided into two main steps: 1) thermal noise-driven gating of the Cx36 hemichannels; 2) binding of Mg2+ ions to and subsequent stabilisation of the closed conformation of the Cx36 hemichannel. The aforementioned data were presented in the paper ‘The Amino Terminal Domain and Modulation of Connexin36 Gap Junction Channels by Intracellular Magnesium Ions’, which was published in the Frontiers in Physiology (IF – 4.755).
Period of project implementation: 2021-04-01 - 2021-12-31
Project partners: Lithuanian University of Health Sciences
