The role of stochastic and modal gating of cardiac L-type Ca2+ channels on early after-depolarizations

Antti J. Tanskanen, Joseph L. Greenstein, Brian O'Rourke, Raimond Winslow

Research output: Contribution to journalArticle

Abstract

Certain signaling events that promote L-type Ca2+ channel (LCC) phosphorylation, such as β-adrenergic stimulation or an increased expression of Ca2+/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 β-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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)85-95
Number of pages11
JournalBiophysical Journal
Volume88
Issue number1
DOIs
StatePublished - Jan 2005

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Action Potentials
Isoproterenol
Muscle Cells
Phosphorylation
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Ryanodine
Adrenergic Agonists
Calcium Channels
Adrenergic Agents
Canidae

ASJC Scopus subject areas

  • Biophysics

Cite this

The role of stochastic and modal gating of cardiac L-type Ca2+ channels on early after-depolarizations. / Tanskanen, Antti J.; Greenstein, Joseph L.; O'Rourke, Brian; Winslow, Raimond.

In: Biophysical Journal, Vol. 88, No. 1, 01.2005, p. 85-95.

Research output: Contribution to journalArticle

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