Abstract
In cardiac myocyte, binding of catecholamine to β1-adrenergic receptor activates protein kinase A (PKA) via G protein (Gs) and adenylyl cyclase that synthesizes cyclic AMP (cAMP). PKA, when activated by cAMP, phosphorylates a wide spectrum of target proteins including L-type Calcium channel, phospholamban, contracting proteins, and ryanodine receptor. Thus, the β-adrenergic signaling pathway dynamically regulates excitation-contraction (E-C) coupling through a combination of feedforward and feedback mechanisms. To understand mechanisms of β1-adrenergic signaling pathway in cardiac E-C coupling quantitatively, we have modeled the β1-adrenergic signaling pathway based on Saucerman et al. (J. Biol. Chem. 2003; 278 47997-48003, and Prog. Biophys. Mol. Biol. 2004; 85 261-78) and incorporated in the Kyoto model which includes cardiac E-C coupling and ATP metabolism (Prog. Biophys. Mol. Biol. 2004; 85 279-299). The parameters of the β1-adrenergic signaling pathway model were modified to fit a wide range of experimental data, and new kinetic models of target protein phosphorylation by PKA, such as phospholamban and L-type Calcium channel were constructed. The β agonist, isoproterenol, dependence of E-C coupling was simulated using this model. [Jpn J Physiol 55 Suppl:S89 (2005)]
