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Science 1 March 2002:
Vol. 295. no. 5560, pp. 1711 - 1715
DOI: 10.1126/science.1069982
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Reports

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}unipd.it

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Localization of Functional Endothelin Receptor Signaling Complexes in Cardiac Transverse Tubules.
V. G. Robu, E. S. Pfeiffer, S. L. Robia, R. C. Balijepalli, Y. Pi, T. J. Kamp, and J. W. Walker (2003)
J. Biol. Chem. 278, 48154-48161
   Abstract »    Full Text »    PDF »
Regulation of T-Cell Activation by Phosphodiesterase 4B2 Requires Its Dynamic Redistribution during Immunological Synapse Formation.
J. Arp, M. G. Kirchhof, M. L. Baroja, S. H. Nazarian, T. A. Chau, C. A. Strathdee, E. H. Ball, and J. Madrenas (2003)
Mol. Cell. Biol. 23, 8042-8057
   Abstract »    Full Text »    PDF »
What Is the Role of {beta}-Adrenergic Signaling in Heart Failure?.
M. J. Lohse, S. Engelhardt, and T. Eschenhagen (2003)
Circ. Res. 93, 896-906
   Abstract »    Full Text »    PDF »
The Expression of the Thyroid-stimulating Hormone (TSH) Receptor and the cAMP-dependent Protein Kinase RII {beta} Regulatory Subunit Confers TSH-cAMP-dependent Growth to Mouse Fibroblasts.
A. Porcellini, S. Messina, G. De Gregorio, A. Feliciello, A. Carlucci, M. Barone, A. Picascia, A. De Blasi, and E. V. Avvedimento (2003)
J. Biol. Chem. 278, 40621-40630
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Lowering Cyclic Adenosine-3',5'-Monophosphate (cAMP) Levels by Expression of a cAMP-Specific Phosphodiesterase Decreases Intrinsic Pulsatile Gonadotropin-Releasing Hormone Secretion from GT1 Cells.
H. Yoshida, L. Beltran-Parrazal, P. Butler, M. Conti, A. C. Charles, and R. I. Weiner (2003)
Mol. Endocrinol. 17, 1982-1990
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Differential relaxing responses to particulate or soluble guanylyl cyclase activation on endothelial cells: a mechanism dependent on PKG-I{alpha} activation by NO/cGMP.
F. J. Rivero-Vilches, S De Frutos, M Saura, D Rodriguez-Puyol, and M Rodriguez-Puyol (2003)
Am J Physiol Cell Physiol 285, C891-C898
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The PDZ-binding motif of the {beta}2-adrenoceptor is essential for physiologic signaling and trafficking in cardiac myocytes.
Y. Xiang and B. Kobilka (2003)
PNAS 100, 10776-10781
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Role of cyclic nucleotide phosphodiesterase isoforms in cAMP compartmentation following {beta}2-adrenergic stimulation of ICa,L in frog ventricular myocytes.
J. Jurevicius, V A. Skeberdis, and R. Fischmeister (2003)
J. Physiol. 551, 239-252
   Abstract »    Full Text »    PDF »
A-kinase anchoring proteins and neuronal signaling mechanisms.
G. K. Carnegie and J. D. Scott (2003)
Genes & Dev. 17, 1557-1568
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T-Tubule Function in Mammalian Cardiac Myocytes.
F. Brette and C. Orchard (2003)
Circ. Res. 92, 1182-1192
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Phosphodiesterase Regulation Is Critical for the Differentiation and Pattern of Gene Expression in Granulosa Cells of the Ovarian Follicle.
J.-Y. Park, F. Richard, S.-Y. Chun, J.-H. Park, E. Law, K. Horner, S-L C. Jin, and M. Conti (2003)
Mol. Endocrinol. 17, 1117-1130
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Developmental Changes in {beta}2-Adrenergic Receptor Signaling in Ventricular Myocytes: the Role of Gi proteins and Caveolae Microdomains.
V. O. Rybin, E. Pak, S. Alcott, and S. F. Steinberg (2003)
Mol. Pharmacol. 63, 1338-1348
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