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Front Pharmacol. 2014 Jan 27;5:5. doi: 10.3389/fphar.2014.00005. eCollection 2014.

The role of CaMKII regulation of phospholamban activity in heart disease.

Author information

1
Facultad de Medicina, Centro de Investigaciones Cardiovasculares, Conicet La Plata-Universidad Nacional de La Plata La Plata, Argentina.
2
Department of Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati Cincinnati, OH, USA.

Abstract

Phospholamban (PLN) is a phosphoprotein in cardiac sarcoplasmic reticulum (SR) that is a reversible regulator of the Ca(2) (+)-ATPase (SERCA2a) activity and cardiac contractility. Dephosphorylated PLN inhibits SERCA2a and PLN phosphorylation, at either Ser(16) by PKA or Thr(17) by Ca(2) (+)-calmodulin-dependent protein kinase (CaMKII), reverses this inhibition. Through this mechanism, PLN is a key modulator of SR Ca(2) (+) uptake, Ca(2) (+) load, contractility, and relaxation. PLN phosphorylation is also the main determinant of β1-adrenergic responses in the heart. Although phosphorylation of Thr(17) by CaMKII contributes to this effect, its role is subordinate to the PKA-dependent increase in cytosolic Ca(2) (+), necessary to activate CaMKII. Furthermore, the effects of PLN and its phosphorylation on cardiac function are subject to additional regulation by its interacting partners, the anti-apoptotic HAX-1 protein and Gm or the anchoring unit of protein phosphatase 1. Regulation of PLN activity by this multimeric complex becomes even more important in pathological conditions, characterized by aberrant Ca(2) (+)-cycling. In this scenario, CaMKII-dependent PLN phosphorylation has been associated with protective effects in both acidosis and ischemia/reperfusion. However, the beneficial effects of increasing SR Ca(2) (+) uptake through PLN phosphorylation may be lost or even become deleterious, when these occur in association with alterations in SR Ca(2) (+) leak. Moreover, a major characteristic in human and experimental heart failure (HF) is depressed SR Ca(2) (+) uptake, associated with decreased SERCA2a levels and dephosphorylation of PLN, leading to decreased SR Ca(2) (+) load and impaired contractility. Thus, the strategy of altering SERCA2a and/or PLN levels or activity to restore perturbed SR Ca(2) (+) uptake is a potential therapeutic tool for HF treatment. We will review here the role of CaMKII-dependent phosphorylation of PLN at Thr(17) on cardiac function under physiological and pathological conditions.

KEYWORDS:

CaMKII; PLN regulation; acidosis; heart failure; ischemia/reperfusion injury; myocardium

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