Roles of Phosphodiesterases in Cyclic Nucleotide Cross-Talk in Cardiac Myocytes

Abstract

The cyclic nucleotides (cNs) cAMP and cGMP regulate the response of cardiac myocytes to both external and internal stimuli. Distinctly-regulated phosphodiesterases (PDEs) control the degradation of these cNs. As a result of their regulation by cNs, PDEs also facilitate communication between the β-adrenergic and Nitric Oxide (NO)/cGMP/Protein Kinase G (PKG) signaling pathways, which regulate the synthesis of cAMP and cGMP, respectively. Activation of the β-adrenergic pathway potentiates cardiac contractility, whereas activation of the NO/cGMP/PKG pathway reduces it. As a result, the balance between cNs plays a critical role in regulating contraction. The phenomena where cAMP influences the dynamics of the cGMP pathway, and vice versa, are commonly referred to as cN cross-talk. However, the cross-talk response and the individual role of each PDE isoenzyme in shaping this response remain to be fully characterized. We have developed a computational model of the cN cross-talk network that mechanistically integrates the β-adrenergic and NO/cGMP/PKG pathways via regulation of PDEs by both cNs. The individual model components and the entire network model replicate experimentally observed activation-response relationships and temporal dynamics. The model predicts that under sub-maximal β-adrenergic stimulation, an increase of PDE2 and a decrease of PDE3 cAMP hydrolysis rates under concomitant NO stimulation results in a net cAMP accumulation, leading to the observed NO-mediated potentiation of Protein Kinase A (PKA) activation. In addition, under concomitant β-adrenergic stimulation, due to cGMP accumulation from increased PDE5 and decreased PDE3 cGMP hydrolysis rates, PKG can be further activated beyond the level achieved under NO alone. By defining cN cross-talk reactions based on the binding affinity of cNs to specific PDE domains and the associated hydrolysis rates, we pin-pointed the principal mechanisms driving the cross-talk response within this non-linear, tightly-coupled reaction system.