Role of phospholamban phosphorylation on Thr17 in cardiac physiological and pathological conditions

Abstract

The sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a) is under the control of a closely associated SR protein named phospholamban (PLN). Dephosphorylated PLN inhibits the SR Ca(2+) pump, whereas phosphorylation of PLN, at either Ser(16) by PKA or Thr(17) by calmodulin-dependent protein kinase II (CaMKII), reverses this inhibition, thus increasing SERCA2a activity and the rate of Ca(2+) uptake by the SR. This would in turn lead to an increase in the velocity of relaxation, SR Ca(2+) load, and myocardial contractility. Thus, PLN is a major determinant of cardiac contractility and relaxation. Although in the intact heart, beta-adrenoceptor stimulation results in phosphorylation of PLN at both Ser(16) and Thr(17) residues, the role of Thr(17) site has long remained equivocal. In this review, we attempt to highlight the signaling cascade and the physiological relevance of the phosphorylation of this residue in the heart under both physiological and pathological situations.

CD36 Protein Influences Myocardial Ca2+ Homeostasis and Phospholipid Metabolism

“…Phosphorylation of PLN by protein kinase A (PKA) reverses the inhibition and increases SERCA activity and the rate of SR Ca 2ϩ uptake (56). Expression levels of these key Ca 2ϩ -handling proteins were examined in hearts from CD36…”

α-Kinase Anchoring Protein αKAP Interacts with SERCA2A to Spatially Position Ca2+/Calmodulin-dependent Protein Kinase II and Modulate Phospholamban Phosphorylation

“…Furthermore, ␣KAP can modulate PLN phosphorylation at Thr-17, which is known to regulate SERCA2a activity and SR function (18,(25)(26)(27)(28). SERCA2a binds directly to regions in the association domain of ␣KAP that are distinct from those that associate with CaMKII.…”

“…cardiac isoform of CAMKII that is targeted to the SR and SERCA2a through ␣KAP. We sought to determine the ability of CaMKII␤ 4 to phosphorylate phospholamban, which is a known regulator of SERCA2a activity and muscle relaxation (18,(25)(26)(27)(28). The ability of CaMKII (␦ C or ␤ 4 ) to phosphorylate SERCA2a or its subunit phospholamban was examined in HeLa cells that were co-transfected with SERCA2a-GFP, ␣KAP-Myc, and CaMKII-Myc isoforms (␦ C or ␤ 4 ).…”

“…It is notable that no phosphorylation of the SERCA2a-GFP (ϳ140-kDa polypeptide), which was co-expressed in these cells, was detected due to CaMKII␦ C or CaMKII␤ 4 activity under these conditions. The CaMKII␦ C is known to phosphorylate Thr-17 on phospholamban and stimulate SERCA2a (18). We examined whether CaMKII␤ 4 can also serve to phosphorylate phospholamban by co-expressing PLN together with CaMKII␦ C or CaMKII␤ 4 as GST fusion proteins and assaying for the Ca 2ϩ / CaM-dependent phosphorylation of PLN as described above.…”

“…Further, studies suggest that CaMKII␤ 4 can recruit the glycolytic machinery to the SR membrane in cardiac and skeletal muscle and potentially serve to spatially modulate the supply of ATP for the calcium transport process (13,14). In view of the emerging concept of spatial and temporal control of signal transduction through kinase-anchoring proteins, we investigated further the role of ␣KAP at the SR membrane and found that it directly interacts with the calcium ATPase and serves to recruit CaMKII isoforms and modulate the phosphorylation of PLN at Thr-17, which is known to critically regulate calcium uptake and muscle relaxation (18). We propose a model in which ␣KAP would serve to modulate PLN phosphorylation and integrate the spatial and temporal control on calcium transport through direct binding to the calcium ATPase on the one hand and recruitment of CaMKII activity on the other.…”