Modeling the actions of β-adrenergic signaling on excitation- contraction coupling processes

Joseph L. Greenstein, Antti J. Tanskanen, Raimond Winslow

Research output: Contribution to journalArticle

Abstract

Activation of the β-adrenergic (β-AR) signaling pathway enhances cardiac function through protein kinase A (PKA)-mediated phosphorylation of target proteins involved in the process of excitation-contraction (EC) coupling. Experimental studies of the effects of β-AR stimulation on EC coupling have yielded complex results, including increased, decreased, or unchanged EC coupling gain. In this study, we extend a previously developed model of the canine ventricular myocyte describing local control of sarcoplasmic reticuium (SR) calcium (Ca2+) release to include the effects of β-AR stimulation. Incorporation of phosphorylation-dependent effects on model membrane currents and Ca2+-cycling proteins yields changes of action potential (AP) and Ca2+ transients in agreement with those measured experimentally in response to the nonspecific β-AR agonist isoproterenol (ISO). The model reproduces experimentally observed alterations in EC coupling gain in response to β-AR agonists and predicts the specific roles of L-type Ca2+ channel (LCC) and SR Ca2+ release channel phosphorylation in altering the amplitude and shape of the EC coupling gain function. The model also indicates that factors that promote mode 2 gating of LCCs, such as β-AR stimulation or activation of the Ca2+/ calmodulin-dependent protein kinase II (CaMKII), may increase the probability of occurrence of early after-depolarizations (EADs), due to the random, long-duration opening of LCC gating in mode 2.

Original languageEnglish (US)
Pages (from-to)16-27
Number of pages12
JournalAnnals of the New York Academy of Sciences
Volume1015
DOIs
StatePublished - 2004

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Keywords

  • Beta-adrenergic signaling
  • Calcium channels
  • Excitation-contraction coupling
  • Phosphorylation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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