title: Modeling the actions of beta-adrenergic signaling on excitation--contraction coupling processes.
abstract: Activation of the beta-adrenergic (beta-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 beta-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 reticulum (SR) calcium (Ca(2+)) release to include the effects of beta-AR stimulation. Incorporation of phosphorylation-dependent effects on model membrane currents and Ca(2+)-cycling proteins yields changes of action potential (AP) and Ca(2+) transients in agreement with those measured experimentally in response to the nonspecific beta-AR agonist isoproterenol (ISO). The model reproduces experimentally observed alterations in EC coupling gain in response to beta-AR agonists and predicts the specific roles of L-type Ca(2+) channel (LCC) and SR Ca(2+) 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 beta-AR stimulation or activation of the Ca(2+)/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.
authors.affiliation: Center for Cardiovascular Bioinformatics and Modeling, The Johns Hopkins University School of Medicine, and Whiting School of Engineering, Baltimore, MD 21218, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Greenstein
authors.forename: Antti J
authors.initials: AJ
authors.lastname: Tanskanen
authors.forename: Raimond L
authors.initials: RL
authors.lastname: Winslow
mesh_terms: D000818:Animals; D004285:Dogs; D009200:Myocardial Contraction; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D011943:Receptors, Adrenergic, beta