The role of CaMKII regulation of phospholamban activity in heart disease

Abstract

Phospholamban (PLN) is a phosphoprotein in cardiac sarcoplasmic reticulum (SR) that is a reversible regulator of the Ca2+-ATPase (SERCA2a) activity and cardiac contractility. Dephosphorylated PLN inhibits SERCA2a and PLN phosphorylation, at either Ser16 by PKA or Thr17 by Ca2+-calmodulin-dependent protein kinase (CaMKII), reverses this inhibition. Through this mechanism, PLN is a key modulator of SR Ca2+ uptake, Ca2+ load, contractility, and relaxation. PLN phosphorylation is also the main determinant of β1-adrenergic responses in the heart. Although phosphorylation of Thr17 by CaMKII contributes to this effect, its role is subordinate to the PKA-dependent increase in cytosolic Ca2+, 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 Ca2+-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 Ca2+ uptake through PLN phosphorylation may be lost or even become deleterious, when these occur in association with alterations in SR Ca2+ leak. Moreover, a major characteristic in human and experimental heart failure (HF) is depressed SR Ca2+ uptake, associated with decreased SERCA2a levels and dephosphorylation of PLN, leading to decreased SR Ca2+ load and impaired contractility. Thus, the strategy of altering SERCA2a and/or PLN levels or activity to restore perturbed SR Ca2+ uptake is a potential therapeutic tool for HF treatment. We will review here the role of CaMKII-dependent phosphorylation of PLN at Thr17 on cardiac function under physiological and pathological conditions.

Ophiopogonin D maintains Ca2+ homeostasis in rat cardiomyocytes in vitro by upregulating CYP2J3/EETs and suppressing ER stress

“…Both OPD and CYP2J3/EETs reversed the down-regulation of these [39] . This phosphorylation prohibits PLB from inhibiting SERCA2a, and Ca 2+ uptake is accelerated.…”

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

“…1d), suggesting that ILK and SERCA-2a protein expression levels are regulated postranscriptionally in DCM. Similarly, SERCA-2a protein levels have been reported as unchanged or decreased in heart failure 20 but are typically observed to be unchanged in DCM 21,22 .…”

“…Overexpression of ILK, using for example gene therapy, would nevertheless be expected to increase SERCA-2a/PLN function and thereby improve cardiac function in DCM through a proteinbinding-dependent mechanism, irrespective of the primary inciting process. The role of CaMKII activation in heart failure has been interpreted as adverse 56 or beneficial and compensatory 20,57 , and the net phenotypic outcome may be dependent upon concomitant activation of interacting signalling pathways. For example, CaMKII signalling may be opposed by activation of calcineurin (Cn)/nuclear factor of activated transcription (NFAT) signalling in a time-and context-dependent manner such that Cn/NFAT signalling and activation (dephosphorylation) of GSK-3b may dominate that of CaMKII only following the transition from adaptive to adverse hypertrophic remodelling 58 .…”

Role of protein phosphorylation in excitation-contraction coupling in taurine deficient hearts

“…However, the effect of heart failure on the phosphorylation status of phospholamban remains controversial. While some investigators observe a decrease in phospholamban phosphorylation secondary to the downregulation of the ␤-adrenergic system and an increase in protein phosphatase 1 activity, other investigators observe either an increase or no change in phospholamban phosphorylation (27). The differences in the phosphorylation status of phospholamban appear to be dependent upon the model of heart failure and the stage of development.…”

“…PKA and Ca 2ϩ -calmodulin dependent protein kinase II (CaMKII) serve as the dominant regulators of phospholamban phosphorylation and SR Ca 2ϩ ATPase activity (27). In the TauTKO heart, PKA activity is normal while the activity of CaMKII is depressed, raising the possibility that the decrease in the phosphorylation state of phospholamban might be caused by a reduction in CaMKII activity.…”