Copyright © 2006, European Society of Cardiology
Phospholamban phosphorylation sites enhance the recovery of intracellular Ca2+ after perfusion arrest in isolated, perfused mouse heart
aCentro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, 60 y 120, (1900) La Plata, Argentina
bDepartment of Physiology, Texas Tech University, Health Science Center, Lubbock, TX 79430, USA
cDepartment of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0575, USA
* Corresponding author. Tel./fax: +54 221 483 4833. Email address: valverdeca{at}atlas.med.unlp.edu.ar
Objective To investigate the importance of the phosphorylation of Ser16 and Thr17 sites of phospholamban (PLN) on intracellular Ca2+ (Cai
) handling and contractile recovery of the stunned myocardium.
Methods Cai (Rhod-2, pulsed local-field fluorescence microscopy) and contractility (isovolumic left ventricular developed pressure, LVDP) were simultaneously measured in Langendorff perfused hearts from transgenic mice expressing either intact PLN (PLN-WT) or PLN with both phosphorylation sites mutated to Ala (PLN-DM), subjected to 12 min of global ischemia followed by a reperfusion period of 30 min.
Results Pre-ischemic values of Cai and LVDP were similar in both groups. In PLN-WT, a transient increase in Thr17 phosphorylation at early reperfusion preceded a recovery of Ca2+ transient amplitude, virtually completed by the end of reperfusion. LVDP at 30 min reperfusion was 67.9±7.6% of pre-ischemic values, n=14. In contrast, in PLN-DM, there was a poor recovery of Cai transient amplitude and LVDP was significantly lower (28.3±6.7%, n=11, 30 min reperfusion) than in PLN-WT hearts. Although myofilament Ca2+ responsiveness and troponin I (TnI) degradation did not differ between groups, the episodes of mechanical alternans, typical of Cai overload, were significantly prolonged in PLN-DM vs. PLN-WT hearts.
Conclusions PLN phosphorylation appears to be crucial for the mechanical and Cai recovery during stunning and protective against the mechanical abnormalities typical of Cai overload. The importance of PLN phosphorylation would primarily reside in the Thr17 residue, which is phosphorylated during the critical early phase of reperfusion. Our results emphasize that, although ablation of PLN phosphorylation does not affect basal contractility, it does alter Ca2+ handling and mechanical performance under stress situations.
KEYWORDS Phospholamban phosphorylation residues; Phospholamban mutants; Intracellular calcium; Ischemia–reperfusion; Myofibrillar proteins
Time for primary review 22 days
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