Regulation of the Cardiac β-Adrenergic Pathway via Camp-Cgmp Competition

Abstract

In the cardiac myocyte, the second messenger cAMP is synthesized by the β-adrenergic signaling pathway upon sympathetic activation. It activates Protein Kinase A (PKA) mediated phosphorylation of downstream targets that are critical to the control of cardiac contractility. The dynamics of cAMP are also controlled indirectly by cGMP-mediated regulation of phosphodiesterase (PDE) isoenzymes. It is not yet clear how the cGMP signal is transduced by the PDEs to regulate cAMP. To better understand this, we have developed mechanistically detailed models of PDEs 1 - 4, the primary cAMP hydrolyzing PDEs in cardiac myocytes, and integrated them into an existing model of the β-adrenergic signaling pathway. Our PDE models are based upon experimental studies performed on purified PDE enzymes which show that cyclic nucleotides (cNs) bind competitively to the domains of PDEs 1, 2, and 3. PDE4 is regulated by PKA but does not interact appreciably with cGMP. Our individual PDE models reproduce cAMP hydrolysis rates as regulated by various cGMP concentrations, and the fully integrated model also replicates experimentally observed cAMP dose-response relationships and temporal dynamics. Our model shows that PDE2 is critical to the regulation of cAMP signals, especially during increased stimulation of the β-adrenergic pathway. In addition, it reveals that high levels of cGMP out-compete cAMP for catalytic sites of PDEs 1, 2, and 3, and suppress their cAMP hydrolysis rates. This leads to a net accumulation of cAMP despite the negative feedback of the cAMP-driven increases in rate of PDE4-mediated cAMP hydrolysis. These results provide insights into how PDEs serve as an integration point for cN signals and how cN interactions regulate β-adrenergic response.