Phosphodiesterases and Compartmentation of cAMP and cGMP Signaling in Regulation of Cardiac Contractility in Normal and Failing Hearts

Figures

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  Figure 1. cAMP/cGMP signaling and PDEs modulating contractility in normal cardiomyocytes. β1-AR stimulation causes a widespread rise in cAMP (cyan), which activates PKA phosphorylation of PLB, TnI, RyR, and LTCC. These events together lead to a positive inotropic response and a positive lusitropic response. Global and localized cAMP pools are under the control of PDE2 (purple), PDE3 (violet), and PDE4 (dark green) activity. β2-AR stimulation increases cAMP (pink), degraded by PDE2, and which affects contractility, but to a lower extent compared to β1-AR stimulation. CNP stimulation of GC-B gives a widespread increase in cGMP (blue) and PKG activation; PKG phosphorylates PLB and TnI and decreases LTCC current. These events contribute to a negative inotropic response and a positive lusitropic response. Global and local cGMP are degraded by PDE2 and PDE3. ANP stimulation of GC-A triggers a more restricted cGMP pool (orange) which does not seem to have a major direct role in contractility, and it is under the control of PDE2 and PDE9. cAMP/cGMP cross-talk is illustrated with black arrows indicating cGMP activation of PDE2 or inhibition of PDE3 activity towards cAMP. β3-AR stimulation can…

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  Figure 2. Remodeling and signaling alterations in heart failure. During HF, cardiomyocytes undergo structural remodeling which leads to alteration of the T-tubule structure, re-organization of the receptors and compartments. Red arrows indicate changes in expression of PDEs while light red arrows indicate changes in ligand and receptor expression in HF. 5-HT4 receptors are increased in HF and their stimulation induces a PIR and LR. Both GC-B and sGC stimulation increases cGMP that inhibits PDE3 activity towards 5-HT4-stimulated cAMP (light green). 5-HT4, 5-HT4 serotonin receptor; other abbreviations as in Figure 1. Created with BioRender.com.