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.