The Presence of Lys27 Instead of Asn27 in Human Phospholamban Promotes Sarcoplasmic Reticulum Ca ²⁺ -ATPase Superinhibition and Cardiac Remodeling

Abstract

Background-Phospholamban (PLN) is an inhibitor of the Ca 2ϩ affinity of sarcoplasmic reticulum (SR) Ca 2ϩ -ATPase (SERCA2). The amino acid sequence of PLN is highly conserved, and although all species contain asparagine (Asn), human PLN is unique in containing lysine (Lys) at amino acid 27. Methods and Results-Human PLN was introduced in the null background. Expression of human PLN, at similar levels to mouse wild-type PLN, resulted in significant decreases in the affinity of SERCA2 for Ca

Silencing calcineurin A subunit reduces SERCA2 expression in cardiac myocytes

“…It is noteworty that the PLB protein of rat cardiac myocytes is mostly present as a pentameric oligomer (Fig. 6C), in agreement with previous reports demonstrating that the PLB monomer-to-pentamer ratio is much lower in murine than in human heart muscle (35). On the other hand, a small band corresponding to PLB monomer appears in TG-treated myocytes (Fig.…”

Highly efficient and specific modulation of cardiac calcium homeostasis by adenovector-derived short hairpin RNA targeting phospholamban

“…This appears to be particularly important in humans, as chronic PLB deficiency owing to genomic mutations was associated with cardiomyopathies. [28][29][30] Whereas in mice complete knockout of PLB (as may also be achieved by RNAi) was able to rescue the severe cardiomyopathic phenotype of MLP knockout mice, 31 suggesting that unregulated PLB silencing is appropriate in this species, application in humans most probably requires regulatable RNAi.…”

Characterizing Phospholamban to Sarco(endo)plasmic Reticulum Ca2+-ATPase 2a (SERCA2a) Protein Binding Interactions in Human Cardiac Sarcoplasmic Reticulum Vesicles Using Chemical Cross-linking

“…Subsequently, in a study in which human PLB was expressed in transgenic mice, Kranias and co-workers concluded that lysine at position 27 makes PLB superinhibitory, inducing heart failure and cardiac remodeling in transgenic mice (38,39). Because of these effects observed in mice, novel functions for PLB in human myocardium were proposed (38,39). However, in the present study, we determined that human PLB (with Lys 27 ) inhibits SERCA2a activity to the same extent as canine PLB, which has Asn 27 .…”