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A model of the L‐type Ca 2+ channel in rat ventricular myocytes: ion selectivity and inactivation mechanisms
Author(s) -
Sun Liang,
Fan JingSong,
Clark John W.,
Palade Philip T.
Publication year - 2000
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1111/j.1469-7793.2000.00139.x
Subject(s) - depolarization , divalent , calmodulin , biophysics , chemistry , ion channel , selectivity , extracellular , membrane potential , myocyte , patch clamp , calcium , biochemistry , biology , endocrinology , receptor , organic chemistry , catalysis
1 We have developed a mathematical model of the L‐type Ca 2+ 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 + , Ca 2+ or Ba 2+ as the majority current carrier. 2 The amplitude of current through the channel is attenuated in the presence of extracellular Ca 2+ or Ba 2+ . 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 Ca 2+ than for Ba 2+ . 3 Decay of the ionic current during maintained depolarization was characterized by means of voltage‐ and Ca 2+ ‐dependent inactivation pathways embedded in a five‐state dynamic channel model. Particularly, Ca 2+ first binds to calmodulin and the Ca 2+ ‐calmodulin complex is the mediator of Ca 2+ inactivation. Ba 2+ ‐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‐shaped curve at higher depolarization levels (>40 mV) in the presence of [Ca 2+ ] o , was observed in double‐pulse protocols used to study channel inactivation. To characterize this phenomenon, a mechanism was incorporated into the model whereby Ca 2+ or Ba 2+ 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 Ca 2+ ‐ 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.