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1 Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Medicas. UNLP, La Plata, Buenos Aires, Argentina
2 Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
* To whom correspondence should be addressed. E-mail: ramattia{at}atlas.med.unlp.edu.ar.
Phosphorylation of phospholamban (PLB) at Ser16 (PKA site) and at Thr17 (CaMKII site), increases sarcoplasmic reticulum Ca2+ uptake and myocardial contractility and relaxation. In perfused rat hearts submitted to ischemia-reperfusion, we previously showed an ischemia-induced Ser16 phosphorylation which was dependent on 
-adrenergic stimulation, and an ischemia and reperfusion-induced Thr17 phosphorylation which was dependent on Ca2+ influx. To elucidate the relationship between these two PLB phosphorylation sites and post-ischemic mechanical recovery, rat hearts were submitted to ischemia-reperfusion in the absence and the presence of the CaMKII inhibitor KN-93 (1 µM), or the -adrenergic blocker dl-propranolol (1 µM). KN-93 diminished the reperfusion-induced Thr17 phosphorylation and depressed the contractile recovery after ischemia. dl-propranolol decreased the ischemia-induced Ser16 phosphorylation but failed to modify the contractile recovery. To obtain further insights into the functional role of the two PLB phosphorylation sites in the post-ischemic mechanical recovery, transgenic mice expressing wild type PLB (PLB-WT), or PLB mutants in which either Thr17 or Ser16 were replaced by Ala (PLB-T17A and PLB-S16A, respectively) into the PLB null background, were used. Both PLB mutants showed a lower contractile recovery than PLB-WT. However, this recovery was significantly impaired all along reperfusion in PLB-T17A, whereas it was depressed only at the beginning of reperfusion in PLB-S16A. Moreover, the recovery of relaxation was delayed in PLB-T17A, whereas it did not change in PLB-S16A, compared to PLB-WT. These findings indicate that although both PLB phosphorylation sites are involved in the mechanical recovery after ischemia, Thr17 appears to play a major role.
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