Compartmentalized phosphodiesterase-2 activity blunts β-adrenergic cardiac inotropy via an NO/cGMP-dependent pathway

被引:226
作者
Mongillo, M
Tocchetti, CG
Terrin, A
Lissandron, V
Cheung, YF
Dostmann, WR
Pozzan, T
Kass, DA
Paolocci, N
Houslay, MD
Zaccolo, M
机构
[1] Venetian Inst Mol Med, I-35129 Padua, Italy
[2] Dulbecco Telechon Inst, I-35129 Padua, Italy
[3] Johns Hopkins Med Inst, Dept Cardiol, Baltimore, MD 21205 USA
[4] Univ Glasgow, Inst Biomed & Life Sci, Div Biochem & Mol Biol, Glasgow, Lanark, Scotland
[5] Univ Vermont, Dept Pharmacol, Burlington, VT USA
[6] Univ Padua, Dept Biomed Sci, Padua, Italy
基金
英国医学研究理事会;
关键词
PDE2; cAMP; cardiomyocytes; fluorescence resonance energy transfer; compartmentalization;
D O I
10.1161/01.RES.0000200178.34179.93
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:226 / 234
页数:9
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