%0 Journal Article %1 Sun_2000_139 %A Sun, L. %A Fan, J. S. %A Clark, J. W. %A Palade, P. T. %D 2000 %J J. Physiol. %K 11080258 Algorithms, Animals, Barium, Calcium Calcium, Channel Channels, Electrophysiology, Gating, Ion L-Type, Membrane Models, Myocardium, Patch-Clamp Permeability, Potentials, Rats, Reticulum, Sarcoplasmi, Sodium, Techniques, Theoretical, c %P 139--158 %T A model of the L-type Ca$^2+$ channel in rat ventricular myocytes: ion selectivity and inactivation mechanisms. %U http://jp.physoc.org/cgi/content/full/529/1/139 %V 529 Pt 1 %X 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 Ba2+ as the majority current carrier. 2. The amplitude of current through the channel is attenuated in the presence of extracellular Ca$^2+$ 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 Ca$^2+$ than for Ba2+. 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. 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 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 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 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.

@article{Sun_2000_139, abstract = {1. We have developed a mathematical model of the L-type {C}a$^{2+}$ 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 {N}a$^{+}$, {C}a$^{2+}$ or Ba2+ as the majority current carrier. 2. The amplitude of current through the channel is attenuated in the presence of extracellular {C}a$^{2+}$ 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 {C}a$^{2+}$ than for Ba2+. 3. Decay of the ionic current during maintained depolarization was characterized by means of voltage- and {C}a$^{2+}$-dependent inactivation pathways embedded in a five-state dynamic channel model. Particularly, {C}a$^{2+}$ first binds to calmodulin and the {C}a$^{2+}$-calmodulin complex is the mediator of {C}a$^{2+}$ 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 [{C}a$^{2+}$]o, was observed in double-pulse protocols used to study channel inactivation. To characterize this phenomenon, a mechanism was incorporated into the model whereby {C}a$^{2+}$ 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 {C}a$^{2+}$- 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.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Sun, L. and Fan, J. S. and Clark, J. W. and Palade, P. T.}, biburl = {https://www.bibsonomy.org/bibtex/212105dfe4f34172539c3ee2b15daf500/hake}, description = {The whole bibliography file I use.}, file = {Sun_2000_139.pdf:Sun_2000_139.pdf:PDF}, interhash = {fb8b5a0eacb9a40b9b753075d8144674}, intrahash = {12105dfe4f34172539c3ee2b15daf500}, journal = {J. Physiol.}, keywords = {11080258 Algorithms, Animals, Barium, Calcium Calcium, Channel Channels, Electrophysiology, Gating, Ion L-Type, Membrane Models, Myocardium, Patch-Clamp Permeability, Potentials, Rats, Reticulum, Sarcoplasmi, Sodium, Techniques, Theoretical, c}, month = Nov, pages = {139--158}, pii = {PHY_0944}, pmid = {11080258}, timestamp = {2009-06-03T11:21:33.000+0200}, title = {A model of the L-type {C}a$^{2+}$ channel in rat ventricular myocytes: ion selectivity and inactivation mechanisms.}, url = {http://jp.physoc.org/cgi/content/full/529/1/139}, volume = {529 Pt 1}, year = 2000 }