Sarcolipin and phospholamban as regulators of cardiac sarcoplasmic reticulum Ca2+ ATPase

Abstract

The cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a) plays a critical role in maintaining the intracellular calcium homeostasis during cardiac contraction and relaxation. It has been well documented over the years that altered expression and activity of SERCA2a can lead to systolic and diastolic dysfunction. The activity of SERCA2a is regulated by two structurally similar proteins, phospholamban (PLB) and sarcolipin (SLN). Although, the relevance of PLB has been extensively studied over the years, the role SLN in cardiac physiology is an emerging field of study. This review focuses on the advances in the understanding of the regulation of SERCA2a by SLN and PLB. In particular, it highlights the similarities and differences between the two proteins and their roles in cardiac patho-physiology.

Fig 1. Schematic representation of homology between the PLB and SLN protein sequence

Horizontal lines denote the membrane boundaries and amino acids are shown in circles using their one letter code (see main text for detailed description)

Fig 2. Sequence comparison of SLN from different species [12, 23]

The amino acids in red differ among the species. The conserved lumenal amino acids are underlined.

Fig 3. Illustration showing differences in the functional effect of PLB and SLN on SR Ca²⁺ uptake

Inhibitory effect of PLB overexpression (PLB O.E) on SERCA calcium uptake is relieved at high calcium concentrations [42] where as SLN overexpression (SLN O.E) is inhibitory even at high calcium compared to wild type (WT) [46, 47] indicating subtle differences in the mechanism of action of the two regulators.

Fig 4. Proposed model depicting the role of PLB and SLN in mediating β-adrenergic response

Active calcium transport into the SR is facilitated by the SERCA2a pump and its activity is regulated by PLB and SLN .In the ventricle PLB is the principal mediator of the β-adrenergic response. In its dephosphorylated form PLB is an inhibitor of SERCA2a. Phosphorylation of PLB in response to β-adrenergic stimulation by protein kinase A (PKA) or Calcium calmodulin dependent kinase (CAMKII) relieves the inhibitory effect of PLB on SERCA2a. In the atria, SLN predominates and plays an important role in mediating the β-adrenergic response. Phosphorylation of SLN by CAMKII relieves the inhibitory effect of SLN on SERCA2a in the atria, activating SERCA2a leading the atrial muscle relaxation.