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A model of the L-type Ca²⁺ channel in rat ventricular myocytes: ion selectivity and inactivation mechanisms

Liang Sun, Jing-Song Fan*, John W. Clark and Philip T. Palade*

1. We have developed a mathematical model of the L-type Ca²⁺ current, which is based on data from whole-cell voltage clamp experiments on rat ventricular myocytes. Ion substitution methods were employed to investigate the ionic selectivity of the channel. Experiments were configured with Na⁺, Ca²⁺ or Ba²⁺ as the majority current carrier.

2. The amplitude of current through the channel is attenuated in the presence of extracellular Ca²⁺ or Ba²⁺. Our model accounts for channel selectivity by using a modified Goldman-Hodgkin-Katz (GHK) configuration that employs voltage-dependent channel binding functions for external divalent ions. Stronger binding functions were used for Ca²⁺ than for Ba²⁺.

3. Decay of the ionic current during maintained depolarization was characterized by means of voltage- and Ca²⁺-dependent inactivation pathways embedded in a five-state dynamic channel model. Particularly, Ca²⁺ first binds to calmodulin and the Ca²⁺-calmodulin complex is the mediator of Ca²⁺ inactivation. Ba²⁺-dependent inactivation was characterized using the t €same scheme, but with a decreased binding to calmodulin.

4. A reduced amount of steady-state inactivation, as evidenced by a U-shaped curve at higher depolarization levels (>40 mV) in the presence of [Ca²⁺]_o, was observed in double-pulse protocols used to study channel inactivation. To characterize this phenomenon, a mechanism was incorporated into the model whereby Ca²⁺ or Ba²⁺ also inhibits the voltage-dependent inactivation pathway.

5. The five-state dynamic channel model was also used to simulate single channel activity. Calculations of the open probability of the channel model are generally consistent with experimental data. A sixth state can be used to simulate modal activity by way of introducing long silent intervals.

6. Our model has been tested extensively using experimental data from a wide variety of voltage clamp protocols and bathing solution manipulations. It provides: (a) biophysically based explanations of putative mechanisms underlying Ca²⁺- and voltage-dependent channel inactivation, and (b) close fits to voltage clamp data. We conclude that the model can serve as a predictive tool in generating testable hypotheses for further investigation of this complex ion channel.

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