This work was supported by Telethon Italy (TCP00089 and GGP05113), the Italian Cystic Fibrosis Research Foundation and the Fondazione Compagnia di San Paolo and the HFSPO (RGP0001/2005-C).
University of Heidelberg (2006) Proc Physiol Soc 4, SA6
Research Symposium: Manuela Zaccolo1, Marco Mongillo1
1. Dulbecco Telethon Institute c/o Venetian Institute of Molecular Medicine, Padova, Italy.
The sympathetic control over excitation-contraction coupling (ECC) is mediated by the cAMP-PKA signalling pathway. It is becoming increasingly evident that the compartmentalization of the pathway components within specific regions of the cell is pivotal to the specific signalling of the cAMP/PKA transduction system (Tasken & Aandahl, 2004). Very little is known, however, on the intracellular dynamics of cAMP and on how such a freely diffusible second messenger can transduce localized signals and mediate specific responses. By using a FRET-based real-time imaging approach (Zaccolo et al. 2000), we are studying the spatio-temporal dynamics of cAMP in isolated intact living rat cardiac myocytes. We were able to directly visualize microdomains of high cAMP in neonatal myocytes stimulated with catecholamine (Zaccolo & Pozzan, 2002). We found that PDEs have a key role in shaping such intracellular steep gradients. In particular, PDE4 (Mongillo et al. 2004)and PDE2 (Mongillo et al. 2006), rather than PDE3, are responsible for modulating the amplitude and duration of the cAMP response to beta-agonists and the consequent effect on the strength of myocyte contraction. Consistent with their distinct function, we found that PDE3 and PDE2/PDE4 localize to different subcellular compartments.
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