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

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 ventricu lar myocytes. Ion substitution methods were employed to investigate the ion ic selectivity of the channel. Experiments were configured with Na+, Ca2+ o r Ba2+ as the majority current carrier. 2. The amplitude of current through the channel is attenuated in the presen ce of extracellular Ca2+ or Ba2+. Our model accounts for channel selectivit y by using a, modified Goldman-Hodgkin-Katz (GHK) configuration that employ s voltage-dependent channel binding functions for external divalent ions. S tronger binding functions were used for Ca2+ than for Ba2+. 3. Decay of the ionic current during maintained depolarization was characte rized by means of voltage- and Ca2+-dependent inactivation pathways embedde d in a five-state dynamic channel model. Particularly, Ca2+ first binds to calmodulin and the Ca2+-calmodulin complex is the mediator of Ca2+ inactiva tion. Ba2+-dependent inactivation was characterized using the same scheme, but with a decreased binding to calmodulin. 4. A reduced amount of steady-state inactivation, as evidenced by a U-shape d curve at higher depolarization levels (>40 mV) in the presence of [Ca2+]( o), was observed in double-pulse protocols used to study channel inactivati on. 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 ch annel activity. Calculations of the open probability of the channel model a re generally consistent with experimental data. A sixth state can be used t o simulate modal activity by way of introducing long silent intervals. 6. Our model has been tested extensively using experimental data from a wid e variety of voltage clamp protocols and bathing solution manipulations. It provides: (a) biophysically based explanations of putative mechanisms unde rlying Ca2+- and voltage-dependent channel inactivation, and (b) close fits to voltage clamp data. We conclude that the model can serve as a predictiv e tool in generating testable hypotheses for further investigation of this complex ion channel.