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Review
. 2014 Jan 27:5:5.
doi: 10.3389/fphar.2014.00005. eCollection 2014.

The role of CaMKII regulation of phospholamban activity in heart disease

Alicia Mattiazzi  1 , Evangelia G Kranias  2
Affiliations
Review

The role of CaMKII regulation of phospholamban activity in heart disease

Alicia Mattiazzi et al. Front Pharmacol. .

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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Figures

FIGURE 1
FIGURE 1
Phospholamban regulatome. Scheme of the multimeric protein complex constituted by SERCA2a, PLN, HAX-1, PKA, CAMKII, PP1, Inhibitor-1 (I-1), and Hsp20, which reversibly regulates SR Ca2+ transport in the cell. SERCA2a activity is regulated by its reversible inhibitor PLN and the histidine rich Ca2+-binding protein (HRC). Phosphorylation of PLN is mediated by cAMP-dependent protein kinase (PKA) at Ser16 site and Ca2+-calmodulin-dependent protein kinase (CaMKII) at Thr17 site. Dephosphorylation of these sites occurs by protein phosphatase 1 (PP1). The activity of PP1 is regulated by inhibitor-1 (I-1) and Hsp20.
FIGURE 2
FIGURE 2
PKA mediated increase in cytosolic Ca2+ and inhibition of PP1: two prerequisites for CaMKII-dependent phosphorylation of PLN during β1-adrenergic stimulation. PKA-dependent phosphorylation of Ca2+ handling proteins, particularly L-type Ca2+ channel and PLN, produces an increase in cytosolic Ca2+ that is necessary to activate CaMKII and produce CaMKII-dependent phosphorylation. PKA also increases inhibitor-1 and Hsp20 phosphorylation, amplifying the stimulatory effects of β1–adrenergic stimulation on SR Ca2+-transport, relaxation, and contractility.
FIGURE 3
FIGURE 3
(A) Intracellular mechanisms that may contribute to the mechanical recovery during acidosis. Acidosis produces a decrease in myofilament Ca2+ responsiveness which increases diastolic Ca2+ ([Ca2+]d). Activation of NHE and direct acidosis inhibition of Na+-Ca2+ exchanger (NCX), would contribute to the increase in cytosolic Ca2+. Acidosis also inhibits PP1. The simultaneous increase in cytosolic Ca2+ and inhibition of PP1 activates CaMKII and enhances PLN phosphorylation at Thr17 site. As a consequence, there is an increase in SR Ca2+ uptake, able to offset the direct acidosis-induced inhibition of SERCA2a activity. This would lead to enhanced SR Ca2+ release and Ca2+ transients, which counteract the negative effect of acidosis on contractile proteins and supply the substrate for the slow mechanical recovery during acidosis. (B). Putative intracellular mechanisms of post-acidosis induced-arrhythmias. Upon returning to control pH, the inhibitory effects of acidosis are rapidly removed, favoring the increase in Ca2+ cycling and the contractile recovery towards control levels. However, the relief of RyR2 from the previous constrain produced by acidosis, evokes also an increase in diastolic Ca2+ leak from the (Ca2+-loaded) SR. Such release may activate inward currents through the NCX, also relieved from the inhibition evoked by acidosis. The inward Na+ current, if large enough, can trigger arrhythmias.
FIGURE 4
FIGURE 4
The beneficial or detrimental effects of CaMKII activation and PLN phosphorylation in I/R depend on a tight balance between SR Ca2+ reuptake and leak. Reperfusion after a short ischemic period (stunning) is associated with an increase in CaMKII-dependent PLN and RyR2 phosphorylation. During early reperfusion (A), there is: abrupt release of SR Ca2+ (inset of the Figure, Valverde et al., 2010), possibly favored by the ischemia-induced increase in SR Ca2+ content; relief of RyR2 inhibition exerted by the ischemic acidosis; and increase in Ser2814 phosphorylation of RyR2 (Said et al., 2011). CaMKII-dependent phosphorylation of PLN does not counteract SR Ca2+ release, which is partially responsible for early reperfusion arrhythmias. (B) After the first minutes of reperfusion, the increase in Thr17 phosphorylation of PLN appears to successfully counteract SR Ca2+ leak, leading to Ca2+ transients and mechanical recovery.
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