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Received September 9, 2004
Revised October 13, 2004
Accepted after revision October 21, 2004
1 Centro de Investigaciones Cardiovasculares. Facultad de Ciencias Medicas. UNLP
2 Centro de Investigaciones Cardiovasculares
* To whom correspondence should be addressed. E-mail: ramattia{at}atlas.med.unlp.edu.ar.
An increase in stimulation frequency causes an acceleration of myocardial relaxation (FDAR). Several mechanisms have been postulated to explain this effect, among which is the CaMKII-dependent phosphorylation of the Thr17 site of phospholamban (PLN). To gain further insights into the mechanisms of FDAR, we studied the FDAR and the phosphorylation of PLN residues in perfused rat hearts, cat papillary muscles and isolated myocytes. This allowed us to sweep over a wide range of frequencies, in species with either positive or negative force-frequency relationships, as well as to explore the FDAR under isometric (or isovolumic) and isotonic conditions. Results were compared with those produced by isoproterenol, an intervention known to accelerate relaxation (IDAR) via PLN phosphorylation. Whereas IDAR occurs tightly associated with a significant increase in the phosphorylation of Ser16 and Thr17 of PLN, FDAR occurs without significant changes in the phosphorylation of PLN residues in the intact heart and cat papillary muscles. Moreover, in intact hearts, FDAR was not associated with any significant change in the CaMKII-dependent phosphorylation of SERCA2a, and was not affected by the presence of the CaMKII inhibitor, KN-93. In isolated myocytes, FDAR occurred associated with an increase in Thr17 phosphorylation. However for a similar relaxant effect produced by isoproterenol, the phosphorylation of PLN (Ser16 + Thr17) was significantly higher in the presence of the 
-agonist. Moreover, the time course of Thr17 phosphorylation was significantly delayed with respect to the onset of FDAR. In contrast, the time course of Ser16 phosphorylation, the first residue that becomes phosphorylated with isoproterenol, was temporally associated with IDAR. Furthermore, KN-93, significantly decreased the phosphorylation of Thr17 evoked by increasing stimulation frequency, but failed to affect FDAR. Taken together, the results provide direct evidence indicating that CaMKII-phosphorylation pathways are not involved in FDAR and that FDAR and IDAR do not share a common underlying mechanism. More likely, a CaMKII-independent mechanism, whereby increasing stimulation frequency would disrupt the SERCA2a-PLN interaction, leading to an increase in SR Ca2+ uptake and myocardial relaxation could be involved.
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