Key result
A proposed five-state model of the cardiac gap junction Ca2+ gate, including four open states and one closed state, successfully reproduced experimental findings and allowed normal action potential propagation.
A novel five-state computational model of cardiac gap junctions demonstrates that sequential ion binding is necessary to simulate normal action potential propagation and recovery of gap junction conductance during diastole.
Advances Ca2+-dependent conduction modeling in animal simulations; leaves open human arrhythmia relevance and therapeutic translation.
We addressed the question how Ca2+ transients affect gap junction conductance (Gj) during action potential (AP) propagation by constructing a dynamic gap junction model coupled with a cardiac cell model. The kinetics of the Ca2+ gate was determined based on published experimental findings that the Hill coefficient for the [Ca2+]i-Gj relationship ranges from 3 to 4, indicating multiple ion bindings. It is also suggested that the closure of the Ca2+ gate follows a single exponential time course. After adjusting the model parameters, a two-state (open-closed) model, assuming simultaneous ion bindings, well described both the single exponential decay and the [Ca2+]i-Gj relationship. Using this gap junction model, 30 cardiac cell models were electrically connected in a one-dimensional cable. However, Gj decreased in a cumulative manner by the repetitive Ca2+ transients, and a conduction block was observed. We found that a reopening of the Ca2+ gate is possible only by assuming a sequential ion binding with one rate limiting step in a multistate model. In this model, the gating time constant (T) has a bell-shaped dependence on [Ca2+]i, with a peak around the half-maximal concentration of [Ca2+]i. Here we propose a five-state model including four open states and one closed state, which allows normal AP propagation; namely, the Gj is decreased -15% by a single Ca2+ transient, but well recovers to the control level during diastole. Under the Ca(2+)-overload condition, however, the conduction velocity is indeed decreased as demonstrated experimentally. This new gap junction model may also be useful in simulations of the ventricular arrhythmia.
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Oka et al. (2006) studied Cardiac gap junction channel gating. Five-state model of Ca2+ gating vs. Two-state model was evaluated on Action potential propagation and gap junction conductance recovery. A proposed five-state model of the cardiac gap junction Ca2+ gate, including four open states and one closed state, successfully reproduced experimental findings and allowed normal action potential propagation.
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