Local control of β-adrenergic stimulation: Effects on ventricular myocyte electrophysiology and Ca2+-transient

Local signaling domains and numerous interacting molecular pathways and substrates contribute to the whole-cell response of myocytes during beta-adrenergic stimulation (beta ARS). We aimed to elucidate the quantitative contribution of substrates and their local signaling environments during beta ARS to the canine epicardial ventricular myocyte electrophysiology and calcium transient (CaT). We present a computational compartmental model of beta ARS and its electrophysiological effects. Novel aspects of the model include localized signaling domains, incorporation of beta 1 and beta 2 receptor isoforms, a detailed population-based approach to integrate the beta AR and Ca2+/Calmodulin kinase (CaMKII) signaling pathways and their effects on a wide range of substrates that affect whole-cell electrophysiology and CaT. The model identifies major roles for phosphodiesterases, adenylyl cyclases, PKA and restricted diffusion in the control of local cAMP levels and shows that activation of specific cAMP domains by different receptor isoforms allows for specific control of action potential and CaT properties. In addition, the model predicts increased CaMKII activity during beta ARS due to rate-dependent accumulation and increased Ca2+ cycling. CaMKII inhibition, reduced compartmentation, and selective blockade of beta 1AR is predicted to reduce the occurrence of delayed afterdepolarizations during beta ARS. Finally, the relative contribution of each PKA substrate to whole-cell electrophysiology is quantified by comparing simulations with and without phosphorylation of each target. In conclusion, this model enhances our understanding of localized beta AR signaling and its whole-cell effects in ventricular myocytes by incorporating receptor isoforms, multiple pathways and a detailed representation of multiple-target phosphorylation; it provides a basis for further studies of beta ARS under pathological conditions.