essfully reproduces cAMP dynamics, activation of adenylyl cyclases and phosphodiesterases, protein kinase A and its targets, voltage-clamp protocols for major repolarization currents, action potential modification, and changes in the Ca2+ handling mechanism upon stimulation of the b1-adrenergic signaling system. The model allows for elucidation of the mechanisms of action potential Adrenergic Signaling in Mouse Myocytes prolongation and increase in i transients. Simulations also show the absence of the negative staircase effect in i transients upon stimulation of b1-adrenoceptors, which was found experimentally. The model also allows for some testable predictions, such as frequency dependences of action potential durations and i transient amplitudes. The model highlights the importance of compartmentalization of the b1-adrenergic signaling system in mouse ventricular myocytes by the description of the two populations of the L-type Ca2+ channels, in caveolae and extracaveolae compartments, and their distinct functional role in myocyte function, as well as the differential localization and function of other PKA targets. Compartmentalization of the b1-adrenergic Signaling System The b-adrenergic signaling system plays a significant role in the function of the heart. There are two types of b-adrenergic receptors in cardiomyocytes, which are different in their cellular localization and function. Experimental data from rat ventricular myocytes by Rybin et al. shows that b1-adrenergic receptors are distributed between caveolae, non-caveolae membrane fractions, and internal membranes, with the majority of the b1-adrenergic receptors being found outside of the caveolae compartment. In contrast, b2-adrenergic receptors are localized in the caveolae compartment. PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19638506 Similar data were obtained PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19638617 for mouse ventricular myocytes. According to the experimental finding, our model includes only 1% of b1-adrenergic receptors in the caveolae compartment, with the majority of them distributed between the extracaveolae and cytosolic compartments. Such localization suggests different functional consequences: selective activation of b1-adrenergic receptors with BAY41-2272 isoproterenol in mouse ventricular myocytes leads to a significant increase in i transient and myocyte contraction, while selective activation of b2adrenergic receptors with zinterol does not have any effect on myocyte contractility. Activation of b1-adrenergic receptors also results in phosphorylation of major cytosolic proteins, such as phospholamban and troponin I, while stimulation of b2-adrenergic receptors does not produce this effect. In addition to differential localization of b1- and b2-adrenergic receptors, experimental data also demonstrates differential localization of signaling proteins involved in the b1-adrenergic signaling pathway, suggesting that even activation of one signaling system is a complex process, which proceeds differently in separate compartments. It has been found that adenylyl cyclases of type V/VI are predominantly localized in caveolae, while types IV and VII are located in non-caveolae membrane fractions and cytosol. There is also differential distribution of three major types of phosphodiesterases in subcellular compartments, which also causes different effects on cAMP degradation. Our model successfully reproduces the activities of ACs and PDEs in different compartments, and the differential effects of PDE3 and PDE4 inhibition in production of cAMP transients. For example,