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 β-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).

Dipeptidyl Peptidase 4 Inhibition Alleviates Shortage of Circulating Glucagon-Like Peptide-1 in Heart Failure and Mitigates Myocardial Remodeling and Apoptosis via the Exchange Protein Directly Activated by Cyclic AMP 1/Ras-Related Protein 1 Axis

“…TAC upregulated the Akt/mTOR/S6K axis ( Figure 1B-1D) and MYH 7 ( Figure 1J), a thick filament protein that controls myofilament Ca 2+ sensitivity via PKA 14 signaling, and this effect was prevented by ALO. The level of phosphorylated phospholamban, which is regulated by PKA, 15 was decreased in TAC, and this effect was reversed by ALO ( Figure 1H). In contrast, AMPK, ERK, MYH 6, troponin T-C, troponin I, and SERCA2a were upregulated in TAC but insensitive to ALO ( Figure II in the Data Supplement; Figure 1E-1G and 1I).…”

Membranes as possible pacemaker of metabolism in cypriniform fish: does phylogeny matter?

“…In addition to being itself a transmembrane protein of the sarcoplasmic reticulum, it is regulated by several membrane-bound proteins that include sarcolipin and phospholamban (Cerra and Imbrogno, 2012;Gorski et al, 2013). If the membrane pacemaker concept accurately predicts cypriniform biochemistry, Ca 2+ -ATPase activity should vary with body mass and/or membrane composition.…”

A Calcium Paradox in the Context of Neurotransmission

“…In addition, a large body of literature discusses the regulation of VACCs in various cell types through their phosphorylation by PKA, including chromaffin cells [55]. Conversely, the cAMP pathway significantly regulates the machinery responsible for the clearance of the [Ca 2+ ]c transients elicited by cell stimulation [56]. Most Ca 2+ clearance during cell stimulation and at the end of the stimulation period is mediated by the PMCA (plasma membrane Ca 2+ ATPase pump) and the plasmalemmal NCX (Na + /Ca 2+ exchanger) isoforms that are particularly active in cardiac myocytes, neurons and the kidney.…”

“…Most Ca 2+ clearance during cell stimulation and at the end of the stimulation period is mediated by the PMCA (plasma membrane Ca 2+ ATPase pump) and the plasmalemmal NCX (Na + /Ca 2+ exchanger) isoforms that are particularly active in cardiac myocytes, neurons and the kidney. The main exchanger isoform is NCX1 that has several splice variants [56,57]. Various studies suggested that the cardiac NCX can be phosphorylated by PKA on sites located in the large intracellular loop, which increases its activity [57].…”