Modeling the calcium gate of cardiac gap junction channel.
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.
Oka
Chiaki
C
Cell/Biodynamics Simulation Project, Kyoto University, Yoshida-konoe, Sakyo-ku, Kyoto, 606-8501 Japan.
Matsuda
Hiroyuki
H
Sarai
Nobuaki
N
Noma
Akinori
A
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D015220:Calcium Channels / Q000032:analysis / Q000502:physiology*; D017629:Gap Junctions / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D006801:Humans; D015640:Ion Channel Gating; D007700:Kinetics; D008564:Membrane Potentials / Q000502:physiology; D008962:Models, Theoretical; D009206:Myocardium / Q000737:chemistry / Q000166:cytology; D013997:Time Factors
D015220:Calcium Channels