Cellular Biology cGMP Signals Modulate cAMP Levels in a Compartment-Specific Manner to Regulate Catecholamine-Dependent Signaling in Cardiac Myocytes

Rationale: cAMP and cGMP are intracellular second messengers involved in heart pathophysiology. cGMP can potentially affect cAMP signals via cGMP-regulated phosphodiesterases (PDEs). Objective: To study the effect of cGMP signals on the local cAMP response to catecholamines in specific subcellular compartments. and cGMP biosensors to detect cyclic nucleotides levels in specific locales. We found that the compartmentalized, but not the global, cAMP response to isoproterenol is profoundly affected by cGMP signals. The effect of cGMP is to increase cAMP levels in the compartment where the protein kinase (PK)A-RI isoforms reside but to decrease cAMP in the compartment where the PKA-RII isoforms reside. These opposing effects are determined by the cGMP-regulated PDEs, namely PDE2 and PDE3, with the local activity of these PDEs being critically important. The cGMP-mediated modulation of cAMP also affects the phosphorylation of PKA targets and myocyte contractility. Conclusions: cGMP signals exert opposing effects on local cAMP levels via different PDEs the activity of which is exerted in spatially distinct subcellular domains. Inhibition of PDE2 selectively abolishes the negative effects of cGMP on cAMP and may have therapeutic potential. T he second messengers cAMP and cGMP play a key role in heart function both in normal and pathological conditions. cAMP mediates the chronotropic, inotropic and lusitropic effects of catecholamines and is involved in the pathogenesis of a number of conditions including hyper-trophy, arrhythmia and heart failure (HF). 1 cGMP mediates the cardiac effects of nitric oxide (NO) and natriuretic peptides and has been involved both in negative metabolic and inotropic effects 2 as well as in cardioprotective mechanisms. 3 Depending on the underlying disease, treatment for acute HF relies on inotropes, acting on cAMP signal-ing, and vasodilators, acting on cGMP signaling. However, lack of a full understanding of the complexity of these pathways limits therapeutic effectiveness 4 and HF mortality remains high. The reduced intracellular content of cAMP and PKA substrate phosphorylation that normally associates with HF is thought to contribute to the pathophysiology of the disease. However therapy aimed at increasing cAMP levels, although effective in increasing myocardial contractility in the short term, results in increased mortality in the long term 5 and chronic treatment with ␤-adrenergic receptor antagonists, which act to decrease cAMP generation, results in improved survival. 6 To explain this apparent paradox the view is emerging that cAMP signaling is compartmentalized 7,8 and spatial control of signal propagation is paramount for speci-ficity of signaling. …