期刊
BIOPHYSICAL JOURNAL
卷 88, 期 1, 页码 85-95出版社
CELL PRESS
DOI: 10.1529/biophysj.104.051508
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资金
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL061711, R01HL060133, R01HL105239, P50HL052307] Funding Source: NIH RePORTER
- NHLBI NIH HHS [R01 HL061711, R01 HL105239, R01 HL60133, P50 HL52307, R01 HL060133, R01 HL61711] Funding Source: Medline
Certain signaling events that promote L-type Ca2+ channel (LCC) phosphorylation, such as beta-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 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 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.
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