Heterotypic Cx43/Cx45 gap junction channel conductance depends on pulse rate and could rescue from arrhythmogenic activity in cardiac tissue

Abstract

Abstract Introduction Gap junction (GJ) channels, formed of connexin (Cx) proteins, conduit electrical excitation in the heart. It is well established that GJ conductance (gj) depends on transjunctional voltage (Vj), but little is still known about its dynamics during the spread of cardiac excitation. Transitional tissue of atrioventricular (AV) node expresses Cx43 and Cx45, which could form heterotypic GJs, which are highly sensitive to Vj. Purpose Evaluation of heterotypic gj dynamics of Cx43/Cx45 channels during the propagation of excitation in cardiac tissue. Methods The CE-4SM model of cardiac tissue, consisting of discrete cells connected through dynamic GJs, was developed by combining Fenton-Karma equations, which define cardiac excitability (CE), and a 4-state model (4SM) of GJ channel gating, which describes the dependence of gj on Vj and its kinetics. Global optimization methods were applied for 4SM parameter evaluation to fit gj timecourses obtained from electrophysiological recordings. Experiments were performed using dual-whole-cell patch clamp in Novikoff cells, endogenously expressing Cx43, and Hela cells transfected with Cx45. Results We developed a combined cardiac excitability model (CE-4SM), that allowed us to study an interaction between the spread of cardiac excitation and GJ channel voltage. Modeling results shows that during propagation of excitation, the phase difference between each action potential (AP) in adjacent cells, generates two subsequent Vj spikes. First spike causes small decrease of gj, while the second one, a minor increase. These impulses can accumulate into a large overall decay until the impulse rate-dependent steady-state is reached. This phenomenon is caused by variation of delays between APs and consequentially, different durations and amplitudes of Vj spikes developed across GJ channels. Interestingly, such gj decrease was capable of causing drift of spiral wave rotor or termination of fibrillation-like arrhythmia during our modeling experiments. Also, we performed in-vitro experiments to evaluate 4SM model parameters and validate simulation results that showed gj decay at a high pulse rate, which could occur during reentry-like tachycardia. Conclusions Voltage gating of Cx43/Cx45 GJ channels could act as a control circuit, that lowers gj between the transitional cells of AV node at high impulse rate. Presumably, this could help to reduce the conduction or even act as a block of high-rate impulses passing through AV node. Also, such gj decrease could cause a drift of spiral waves and disruption of fibrillation-like processes. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Lithuanian University of Health Sciences, Institute of Cardiology