Thus, increased arginase activity promotes over-all systemic as well as endothelial inflammation

steady-state cAMP concentration is smaller and cAMP transient is less prolonged in the caveolae compartment than in the extracaveolae and cytosol, suggesting larger activity of PDEs in the caveolae. Finally, the major protein kinase A phosphorylation targets are also localized in different subcellular compartments. Two of them are found predominantly in the caveolae compartment, five others are predominantly expressed in non-caveolae membrane domains, and phospholamban and troponin I are located in the cytosol. It is remarkable that one of the PKA targets, the L-type Ca2+ channel, is expressed in both the caveolae and extracaveolae compartments, with different a physiological role in each domain. In addition to the different distribution of two major protein kinase A isoforms, there is also a different localization of the major dephosphorylation proteins. Both PP1 and PP2A are found in the caveolae and cytosolic compartments, however, only PP1 plays an important functional role in the extracaveolae. Such distribution of the targets results in their different phosphorylation kinetics and magnitude, producing a very complex interaction relationship in the effects on action potential and i transients. Our model of the b1-adrenergic signaling system includes purchase SB-366791 differential subcellular localization of both signaling and target proteins, and is able to reproduce both phosphorylation kinetics and concentration-dependence of protein phosphorylation by isoproterenol. Several non-compartmentalized models were developed for b1-adrenergic signaling system in different species, including mice. The models were extensively verified by the available experimental data on the effects of activation of b1-adrenergic receptors on electrical activity and ionic homeostasis. However, as the experimental PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19638617 technique is improving PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19640586 and the new data on subcellular organization of signaling systems is accumulating, more comprehensive models are required for more precise description of the cellular functions. Such important findings include differential localization of the isoforms of the major signaling proteins in the b1-adrenergic signaling system: adenylyl cyclases, phosphodiesterases, and protein kinase A. Discovery of the differential localization of the targets of PKA, such as the ionic currents and contractile proteins, requires more demands on the models of cardiac cells to include multiple subcellular compartments. One of the recent experimental findings of the two populations of the L-type Ca2+ channels, the major players in cardiac excitationcontraction coupling, and their differential physiological role in cellular function highlights the needs in compartmentalized models of cardiac myocytes. One such model was developed recently for canine ventricular myocytes and includes three signaling systems, b1- and b2-adrenergic, and CaMKIImediated signaling systems. The model described well extensive experimental data and the effects of different signaling systems on the cardiac action potential and i transients. Our model of the b1-adrenergic signaling system consists of some elements of the model of Heijman et al., but with significant differences, as outlined above. In particular, the presented model includes different localization of ryanodine receptors and describes two populations of the L-type Ca2+ channels based on the most recent experimental data. While the major role of compartmentalization of the components in the b1-adrenergic signaling system is clear