Modeling the Actions of β‐Adrenergic Signaling on Excitation—Contraction Coupling Processes

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 reticulum (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.