Phospholamban and cardiac function: a comparative perspective in vertebrates

Abstract

Phospholamban (PLN) is a small phosphoprotein closely associated with the cardiac sarcoplasmic reticulum (SR). Dephosphorylated PLN tonically inhibits the SR Ca-ATPase (SERCA2a), while phosphorylation at Ser16 by PKA and Thr17 by Ca 2+ /calmodulin-dependent protein kinase (CaMKII) relieves the inhibition, and this increases SR Ca 2+ uptake. For this reason, PLN is one of the major determinants of cardiac contractility and relaxation. In this review, we attempted to highlight the functional significance of PLN in vertebrate cardiac physiology. We will refer to the huge literature on mammals in order to describe the molecular characteristics of this protein, its interaction with SERCA2a and its role in the regulation of the mechanic and the electric performance of the heart under basal conditions, in the presence of chemical and physical stresses, such as b-adrenergic stimulation, response to stretch, force-frequency relationship and intracellular acidosis. Our aim is to provide the basis to discuss the role of PLN also on the cardiac function of nonmammalian vertebrates, because so far this aspect has been almost neglected. Accordingly, when possible, the literature on PLN will be analysed taking into account the nonuniform cardiac structural and functional characteristics encountered in ectothermic vertebrates, such as the peculiar and variable organization of the SR, the large spectrum of response to stresses and the disaptive absence of crucial proteins (i.e. haemoglobinless and myoglobinless species). Intracellular [Ca 2+ ] oscillation, a major determinant of the myocardial contraction/relaxation cycle, is governed by a number of transporters. They include sarcolemmal L-type Ca 2+ channels, Na + /Ca 2+ exchanger, the plasma membrane Ca 2+ pump, several sarcoplasmic reticulum (SR) membrane proteins such as the ryanodine receptors, as well as the complex formed by the sarcoplasmic membrane Ca 2+ pump (SERCA2a) and its associated regulatory protein phospholamban (PLN). The name of this protein, which means 'phosphate receptor' (from phosphate and the Greek word kalbamx = I receive), very appropriately reflects its function. After its discovery by Katz and co-workers in cardiac mammalian microsomes [for complete references, see Katz (2006)], many works have largely demonstrated that, during a normal cardiac cycle, alternate PLN phosphorylation/dephosphorylation determines SERCA2a on/off state, and thus the rate of SR refilling with Ca 2+ , with a consequent strong impact on myocardial relaxation and contraction. At the level of sinoatrial node cells, the SERCA2a-PLN system functions as an intracellular 'Ca 2+ ' clock,

Myostatin Regulates Tissue Potency and Cardiac Calcium-Handling Proteins

“…phosphorylates PLN (72). Ablation of PLN enhances Ca 2ϩ reuptake and relaxation in cardiac muscle, but also impairs ␤AR sensitivity, whereas PLN overexpression compromises mechanical performance, all of which can be rescued with ␤AR activation.…”

Clinical interpretation of genetic variants in arrhythmogenic right ventricular cardiomyopathy

“…(SERCA) pump in a cardiac muscle [91]. Thus, PLN is one of the key proteins in cardiac contractility and relaxation [92].…”

Tumor necrosis factor alpha protects heart cultures against hypoxic damage via activation of PKA and phospholamban to prevent calcium overload

“…Hypoxic conditions are known to induce an increase in SERCA2a activity via PKA (Cerra and Imbrogno 2012). It is suggested here that the protective mechanism of TNF␣ against hypoxic damage is via the activation of PKA (Figs.…”

“…Phospholamban interacts with SERCA2a and reduces Ca 2+ pump activity in its dephosphorylated state through a reduction in the apparent Ca 2+ affinity to the pump (Cerra and Imbrogno 2012). Cardiomyocytes from failing hearts exhibit reduced levels of SERCA2a and (or) increased activity of the endogenous SERCA2a inhibitor, phospholamban (Louch et al 2012).…”

“…SERCA2a is the most important protein regulating Ca 2+ transport into the SR. Phospholamban is an inhibitor of SERCA2a that increases SERC2a activity upon its phosphorylation (Muller and Dhalla 2010;Cerra and Imbrogno 2012;Kranias and Hajjar 2012). Phospholamban interacts with SERCA2a and reduces Ca 2+ pump activity in its dephosphorylated state through a reduction in the apparent Ca 2+ affinity to the pump (Cerra and Imbrogno 2012).…”