Journal
CIRCULATION RESEARCH
Volume 98, Issue 2, Pages 226-234Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000200178.34179.93
Keywords
PDE2; cAMP; cardiomyocytes; fluorescence resonance energy transfer; compartmentalization
Funding
- Medical Research Council [G8604010] Funding Source: Medline
- NHLBI NIH HHS [R01 HL075265] Funding Source: Medline
- Telethon [TCP00089] Funding Source: Medline
- MRC [G8604010] Funding Source: UKRI
- Medical Research Council [G8604010] Funding Source: researchfish
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beta-Adrenergic signaling via cAMP generation and PKA activation mediates the positive inotropic effect of catecholamines on heart cells. Given the large diversity of protein kinase A targets within cardiac cells, a precisely regulated and confined activity of such signaling pathway is essential for specificity of response. Phosphodiesterases (PDEs) are the only route for degrading cAMP and are thus poised to regulate intracellular cAMP gradients. Their spatial confinement to discrete compartments and functional coupling to individual receptors provides an efficient way to control local [cAMP](i) in a stimulus-specific manner. By performing real-time imaging of cyclic nucleotides in living ventriculocytes we identify a prominent role of PDE2 in selectively shaping the cAMP response to catecholamines via a pathway involving beta(3)-adrenergic receptors, NO generation and cGMP production. In cardiac myocytes, PDE2, being tightly coupled to the pool of adenylyl cyclases activated by beta-adrenergic receptor stimulation, coordinates cGMP and cAMP signaling in a novel feedback control loop of the beta-adrenergic pathway. In this, activation of beta(3)-adrenergic receptors counteracts cAMP generation obtained via stimulation of beta(1)/beta(2)-adrenoceptors. Our study illustrates the key role of compartmentalized PDE2 in the control of catecholamine-generated cAMP and furthers our understanding of localized cAMP signaling.
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