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.
Highlights
A major characteristic of human and experimental heart failure (HF) is altered Ca2+ cycling, associated with decreased contractility, which partially reflects the impaired function of the sarcoplasmic reticulum (SR) membrane
We have described that PLN and its calmodulin-dependent protein kinase II (CaMKII)-dependent phosphorylation are part of a multimeric functionally coupled signaling complex, composed of SERCA, PLN, HS-1 associated protein X-1 (HAX-1), PKA, CaMKII, PP1, I-1, and heat shock protein 20 (Hsp20), which reversibly regulates SR Ca2+ cycling
CaMKII-dependent PLN phosphorylation contributes to β1-adrenergic mechanical response, its role is subordinate to the PKA-dependent increase in cytosolic Ca2+ and inhibition of phosphatase, necessary to activate CaMKII and phosphorylate Thr17 of PLN
Summary
A major characteristic of human and experimental heart failure (HF) is altered Ca2+ cycling, associated with decreased contractility, which partially reflects the impaired function of the sarcoplasmic reticulum (SR) membrane. During a normal excitation-contraction-coupling cycle (ECC), Ca2+ enters the cell through the L-type Ca2+ channels leading to activation of the ryanodine receptors (RyR2) in the SR and release of Ca2+ from this membrane system. PLN can be phosphorylated at three distinct sites in vitro: Ser by cyclic AMP (cAMP)- and cGMP-dependent protein kinases, Thr by Ca2+-calmodulin-dependent protein kinase II (CaMKII), and Ser by protein kinase C (Movsesian et al, 1984; Simmerman et al, 1986; Huggins et al, 1989). Phosphorylation of these sites in vitro relieves the inhibition of PLN on SERCA2a and increases SR Ca2+ uptake. Channel and RyR2 phosphorylation, mediate the enhanced contractility produced by ß1-stimulation
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