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Role of dual-site phospholamban phosphorylation in the stunned heart: insights from phospholamban site-specific mutants

¹Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, 1900 La Plata, Argentina; and ²Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0575

Submitted 6 March 2003 ; accepted in final form 15 May 2003

Phosphorylation of phospholamban (PLB) at Ser¹⁶ (protein kinase A site) and at Thr¹⁷ [Ca²⁺/calmodulin kinase II (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 that was dependent on -adrenergic stimulation and an ischemia and reperfusion-induced Thr¹⁷ phosphorylation that was dependent on Ca²⁺ influx. To elucidate the relationship between these two PLB phosphorylation sites and postischemic mechanical recovery, rat hearts were submitted to ischemia-reperfusion in the absence and 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 recovery of contraction and relaxation 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 postischemic 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 with 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.

phospholamban phosphorylation residues; phospholamban mutants; ischemia-reperfusion

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