Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 285, Issue 3, Pages H1198-H1205Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00209.2003
Keywords
phospholamban phosphorylation residues; phospholamban mutants; ischemia-reperfusion
Funding
- FIC NIH HHS [1R03 TW 06294-01] Funding Source: Medline
- NCRR NIH HHS [P40 RR 12358] Funding Source: Medline
- NHLBI NIH HHS [HL 26057] Funding Source: Medline
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Phosphorylation of phospholamban (PLB) at Ser(16) ( protein kinase A site) and at Thr(17) [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 Ser(16) phosphorylation that was dependent on beta-adrenergic stimulation and an ischemia and reperfusion-induced Thr(17) 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 muM) or the beta-adrenergic blocker dl-propranolol (1 muM). KN-93 diminished the reperfusion-induced Thr(17) phosphorylation and depressed the recovery of contraction and relaxation after ischemia. dl-Propranolol decreased the ischemia-induced Ser(16) 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 Thr(17) or Ser(16) 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, Thr(17) appears to play a major role.
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