title: A model of the L-type Ca2+ channel in rat ventricular myocytes: ion selectivity and inactivation mechanisms.
abstract: 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 ttau 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.
authors.affiliation: Department of Electrical and Computer Engineering, Rice University, Houston, TX 77005-1892, USA.
authors.forename: L
authors.initials: L
authors.lastname: Sun
authors.forename: J S
authors.initials: JS
authors.lastname: Fan
authors.forename: J W
authors.initials: JW
authors.lastname: Clark
authors.forename: P T
authors.initials: PT
authors.lastname: Palade
mesh_terms: D000465:Algorithms; D000818:Animals; D001464:Barium / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D004594:Electrophysiology; D015640:Ion Channel Gating / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D008962:Models, Theoretical; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010539:Permeability; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012964:Sodium / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D001464:Barium; D012964:Sodium; D002118:Calcium