Certain signaling events that promote L-type Ca$^2+$ channel (LCC)
phosphorylation, such as beta-adrenergic stimulation or an increased
expression of Ca$^2+$/calmodulin-dependent protein kinase II,
promote mode 2 gating of LCCs. Experimental data suggest the hypothesis
that these events increase the likelihood of early after-depolarizations
(EADs). We test this hypothesis using an ionic model of the canine
ventricular myocyte incorporating stochastic gating of LCCs and ryanodine-sensitive
calcium release channels. The model is extended to describe myocyte
responses to the beta-adrenergic agonist isoproterenol. Results demonstrate
that in the presence of isoproterenol the random opening of a small
number of LCCs gating in mode 2 during the plateau phase of the action
potential (AP) can trigger EADs. EADs occur randomly, where the likelihood
of these events increases as a function of the fraction of LCCs gating
in mode 2. Fluctuations of the L-type Ca$^2+$ current during
the AP plateau lead to variability in AP duration. Consequently,
prolonged APs are occasionally observed and exhibit an increased
likelihood of EAD formation. These results suggest a novel stochastic
mechanism, whereby phosphorylation-induced changes in LCC gating
properties contribute to EAD generation.
%0 Journal Article
%1 Tans_2005_85
%A Tanskanen, Antti J
%A Greenstein, Joseph L
%A O'Rourke, Brian
%A Winslow, Raimond L
%D 2005
%J Biophys. J.
%K 15501946 AMP-Dependent Acid Action Adaptor Adrenergic, Algorithms, Amino Animals, Biological, Biophysics, Calcium Calcium, Cardiac, Cardiovascular, Cells, Chains, Channels, Complexes, Computer Conduction Cyclic Dependent Dogs, Electrophysiology, Expression Extramural, Factors, Gene Gov't, Guinea Heart Humans, Interaction Ions, Isoproterenol, Kinase, Kinases, L-Type, Long Mapping, Markov Membrane Models, Multiprotein Muscle Myocardium, Myocytes, N.I.H., Neurons, Non-U.S. P.H.S., Phosphatase, Phosphoprotein Phosphorylation, Pigs, Post-Translational, Potassium Potentials, Processes, Processing, Profiling, Protein Proteins, Proteome, Proteomics, QT Receptors, Regulation, Relationship, Research Ryanodine, Signal Simulation, Stochastic Structure-Activity Substitution, Support, Syndrome, System, Time Transducing, Transduction, U.S. Voltage-Gated, beta-1, {C}a$^{2+}$-Calmodulin
%N 1
%P 85--95
%R 10.1529/biophysj.104.051508
%T The role of stochastic and modal gating of cardiac L-type Ca$^2+$
channels on early after-depolarizations.
%U http://dx.doi.org/10.1529/biophysj.104.051508
%V 88
%X Certain signaling events that promote L-type Ca$^2+$ channel (LCC)
phosphorylation, such as beta-adrenergic stimulation or an increased
expression of Ca$^2+$/calmodulin-dependent protein kinase II,
promote mode 2 gating of LCCs. Experimental data suggest the hypothesis
that these events increase the likelihood of early after-depolarizations
(EADs). We test this hypothesis using an ionic model of the canine
ventricular myocyte incorporating stochastic gating of LCCs and ryanodine-sensitive
calcium release channels. The model is extended to describe myocyte
responses to the beta-adrenergic agonist isoproterenol. Results demonstrate
that in the presence of isoproterenol the random opening of a small
number of LCCs gating in mode 2 during the plateau phase of the action
potential (AP) can trigger EADs. EADs occur randomly, where the likelihood
of these events increases as a function of the fraction of LCCs gating
in mode 2. Fluctuations of the L-type Ca$^2+$ current during
the AP plateau lead to variability in AP duration. Consequently,
prolonged APs are occasionally observed and exhibit an increased
likelihood of EAD formation. These results suggest a novel stochastic
mechanism, whereby phosphorylation-induced changes in LCC gating
properties contribute to EAD generation.
@article{Tans_2005_85,
abstract = {Certain signaling events that promote L-type {C}a$^{2+}$ channel (LCC)
phosphorylation, such as beta-adrenergic stimulation or an increased
expression of {C}a$^{2+}$/calmodulin-dependent protein kinase II,
promote mode 2 gating of LCCs. Experimental data suggest the hypothesis
that these events increase the likelihood of early after-depolarizations
(EADs). We test this hypothesis using an ionic model of the canine
ventricular myocyte incorporating stochastic gating of LCCs and ryanodine-sensitive
calcium release channels. The model is extended to describe myocyte
responses to the beta-adrenergic agonist isoproterenol. Results demonstrate
that in the presence of isoproterenol the random opening of a small
number of LCCs gating in mode 2 during the plateau phase of the action
potential (AP) can trigger EADs. EADs occur randomly, where the likelihood
of these events increases as a function of the fraction of LCCs gating
in mode 2. Fluctuations of the L-type {C}a$^{2+}$ current during
the AP plateau lead to variability in AP duration. Consequently,
prolonged APs are occasionally observed and exhibit an increased
likelihood of EAD formation. These results suggest a novel stochastic
mechanism, whereby phosphorylation-induced changes in LCC gating
properties contribute to EAD generation.},
added-at = {2009-06-03T11:20:58.000+0200},
author = {Tanskanen, Antti J and Greenstein, Joseph L and O'Rourke, Brian and Winslow, Raimond L},
biburl = {https://www.bibsonomy.org/bibtex/2ed39b0d194f591105a72acb10642fa6d/hake},
description = {The whole bibliography file I use.},
doi = {10.1529/biophysj.104.051508},
file = {Tans_2005_85.pdf:Tans_2005_85.pdf:PDF},
interhash = {5d193777bb1af552e074c892c486ca6c},
intrahash = {ed39b0d194f591105a72acb10642fa6d},
journal = {Biophys. J.},
keywords = {15501946 AMP-Dependent Acid Action Adaptor Adrenergic, Algorithms, Amino Animals, Biological, Biophysics, Calcium Calcium, Cardiac, Cardiovascular, Cells, Chains, Channels, Complexes, Computer Conduction Cyclic Dependent Dogs, Electrophysiology, Expression Extramural, Factors, Gene Gov't, Guinea Heart Humans, Interaction Ions, Isoproterenol, Kinase, Kinases, L-Type, Long Mapping, Markov Membrane Models, Multiprotein Muscle Myocardium, Myocytes, N.I.H., Neurons, Non-U.S. P.H.S., Phosphatase, Phosphoprotein Phosphorylation, Pigs, Post-Translational, Potassium Potentials, Processes, Processing, Profiling, Protein Proteins, Proteome, Proteomics, QT Receptors, Regulation, Relationship, Research Ryanodine, Signal Simulation, Stochastic Structure-Activity Substitution, Support, Syndrome, System, Time Transducing, Transduction, U.S. Voltage-Gated, beta-1, {C}a$^{2+}$-Calmodulin},
month = Jan,
number = 1,
pages = {85--95},
pii = {biophysj.104.051508},
pmid = {15501946},
timestamp = {2009-06-03T11:21:34.000+0200},
title = {The role of stochastic and modal gating of cardiac L-type {C}a$^{2+}$
channels on early after-depolarizations.},
url = {http://dx.doi.org/10.1529/biophysj.104.051508},
volume = 88,
year = 2005
}