Phospholamban interactome in cardiac contractility and survival: A new vision of an old friend

Abstract

Depressed sarcoplasmic reticulum (SR) calcium cycling, reflecting impaired SR Ca-transport and Ca-release, is a key and universal characteristic of human and experimental heart failure. These SR processes are regulated by multimeric protein complexes, including protein kinases and phosphatases as well as their anchoring and regulatory subunits that fine-tune Ca-handling in specific SR sub-compartments. SR Ca-transport is mediated by the SR Ca-ATPase (SERCA2a) and its regulatory phosphoprotein, phospholamban (PLN). Dephosphorylated PLN is an inhibitor of SERCA2a and phosphorylation by protein kinase A (PKA) or calcium-calmodulin-dependent protein kinases (CAMKII) relieves these inhibitory effects. Recent studies identified additional regulatory proteins, associated with PLN, that control SR Ca-transport. These include the inhibitor-1 (I-1) of protein phosphatase 1 (PP1), the small heat shock protein 20 (Hsp20) and the HS-1 associated protein X-1 (HAX1). In addition, the intra-luminal histidine-rich calcium binding protein (HRC) has been shown to interact with both SERCA2a and triadin. Notably, there is physical and direct interaction between these protein players, mediating a fine-cross talk between SR Ca-uptake, storage and release. Importantly, regulation of SR Ca-cycling by the PLN/SERCA interactome does not only impact cardiomyocyte contractility, but also survival and remodeling. Indeed, naturally occurring variants in these Ca-cycling genes modulate their activity and interactions with other protein partners, resulting in depressed contractility and accelerated remodeling. These genetic variants may serve as potential prognostic or diagnostic markers in cardiac pathophysiology.

STIM1 enhances SR Ca 2+ content through binding phospholamban in rat ventricular myocytes

“…PLN is one of the primary regulators of SERCA2a (27). When PLN binds to SERCA2a, it inhibits the Ca 2+ pumping function and thus reduces the ability of the SR to acquire and store Ca 2+ .…”

“…In the work presented here, we show that STIM1 is present but that its function in heart is distinct from the canonical SOCE behavior and does not contribute to Ca 2+ influx through I SOCE . Instead we show that STIM1 binds phospholamban (PLN), an endogenous SERCA2a inhibitor in the heart (27), and by doing so reduces the PLN-dependent inhibition of SERCA2a and thereby indirectly activates SERCA2a.…”

Myocardial expression profiles of candidate molecules in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia compared to those with dilated cardiomyopathy and healthy controls

“…It has been shown that decreased phosphorylation of PLN, and an increase of the PLN to Ca 2+ ATPase pump ratio leads to contractile dysfunction. 15 In vitro studies have revealed that higher phosphorylation levels of PLN lead to improved contractility, and that its dephosphorylation may promote heart failure. 27 for dysfunctional intercalated discs.…”

“…14 Especially PLN phosphorylation has been reported to play a key role in the pathophysiology of heart failure. 15 Taken together, various cellular pathways, particularly electromechanical cell-to-cell coupling, inflammation, apoptosis, adipogenesis and fibrosis seem to be involved in the pathophysiology of ARVC/D, but the interactions are not fully understood. Therefore, the aim of this study was to identify dysregulated myocardial molecules associated with the mentioned pathways ARVC/D by investigating the myocardial expression profiles of various candidate proteins using an mRNA expression and immunolocalization approach.…”

“…Mother HtTx=heart transplantation; ICD= implantable cardioverter-defibrillator; LBBB= left bundle branch block; LVEF= left ventricular ejection fraction; RVOT= right ventricular outflow tract; SAECG= signal-averaged ECG; SCA= sudden cardiac arrest; VF= ventricular fibrillation; sVT= sustained ventricular tachycardia; nsVT= nonsustained ventricular tachycardia; TFS= task force score, *adapted from Task force criteria according to Marcus et al 15 with each major criterion counting as two points and each minor criterion as one point, at least four points required for definite diagnosis; diagnostic categories; A= global or regional dysfunction with structural alterations; B= tissue characterization; C= repolarization abnormalities; D= depolarization abnormalities; E= arrhythmias; F= family history.…”