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Science 295 (5560): 1711-1715

Copyright © 2002 by the American Association for the Advancement of Science

Discrete Microdomains with High Concentration of cAMP in Stimulated Rat Neonatal Cardiac Myocytes

Manuela Zaccolo,* Tullio Pozzan

The second messenger cyclic adenosine monophosphate (cAMP) is the most important modulator of sympathetic control over cardiac contractility. In cardiac myocytes and many other cell types, however, cAMP transduces the signal generated upon stimulation of various receptors and activates different cellular functions, raising the issue of how specificity can be achieved. In the general field of signal transduction, the view is emerging that specificity is guaranteed by tight localization of signaling events. Here, we show that in neonatal rat cardiac myocytes, beta -adrenergic stimulation generates multiple microdomains with increased concentration of cAMP in correspondence with the region of the transverse tubule/junctional sarcoplasmic reticulum membrane. The restricted pools of cAMP show a range of action as small as approximately 1 micrometer, and free diffusion of the second messenger is limited by the activity of phosphodiesterases. Furthermore, we demonstrate that such gradients of cAMP specifically activate a subset of protein kinase A molecules anchored in proximity to the T tubule.

Department of Biomedical Sciences and Venetian Institute for Molecular Medicine, University of Padua, Via Orus 2, 35129 Padua, Italy.
*   To whom correspondence should be addressed. E-mail: manuela.zaccolo{at}

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A. Schmid, Z. Sutto, M.-C. Nlend, G. Horvath, N. Schmid, J. Buck, L. R. Levin, G. E. Conner, N. Fregien, and M. Salathe (2007)
J. Gen. Physiol. 130, 99-109
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Organization and Ca2+ Regulation of Adenylyl Cyclases in cAMP Microdomains.
D. Willoughby and D. M. F. Cooper (2007)
Physiol Rev 87, 965-1010
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cAMP and cGMP Signaling Cross-Talk: Role of Phosphodiesterases and Implications for Cardiac Pathophysiology.
M. Zaccolo and M. A. Movsesian (2007)
Circ. Res. 100, 1569-1578
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mRNA expression and antilipolytic role of phosphodiesterase 4 in rat adipocytes in vitro.
H. Wang and N. K. Edens (2007)
J. Lipid Res. 48, 1099-1107
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cAMP microdomains and L-type Ca2+ channel regulation in guinea-pig ventricular myocytes.
S. Warrier, G. Ramamurthy, R. L. Eckert, V. O. Nikolaev, M. J. Lohse, and R. D. Harvey (2007)
J. Physiol. 580, 765-776
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cAMP-Specific Phosphodiesterase-4 Enzymes in the Cardiovascular System: A Molecular Toolbox for Generating Compartmentalized cAMP Signaling.
M. D. Houslay, G. S. Baillie, and D. H. Maurice (2007)
Circ. Res. 100, 950-966
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Dynamic Regulation of Cystic Fibrosis Transmembrane Conductance Regulator by Competitive Interactions of Molecular Adaptors.
J. H. Lee, W. Richter, W. Namkung, K. H. Kim, E. Kim, M. Conti, and M. G. Lee (2007)
J. Biol. Chem. 282, 10414-10422
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Regulation of Phosphodiesterase 3 and Inducible cAMP Early Repressor in the Heart.
C. Yan, C. L. Miller, and J.-i. Abe (2007)
Circ. Res. 100, 489-501
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Cyclic Nucleotide Phosphodiesterase (PDE) Inhibitors: Novel Therapeutic Agents for Progressive Renal Disease.
J. Cheng and J. P. Grande (2007)
Experimental Biology and Medicine 232, 38-51
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Genetically encoded Ca2+ indicators: using genetics and molecular design to understand complex physiology.
M. I. Kotlikoff (2007)
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