Inhibitor-1 is Potential Target for Enhancing Sarcoplasmic Reticulum Ca2+ Loading in Failing Hearts

Abstract

ysregulated Ca 2+ homeostasis is a hallmark of heart failure that is directly linked to cardiac dysfunction and lethal arrhythmia. 1 It is associated with imbalance of kinases/phosphatase activities in the corresponding intracellular microdomains, leading to either hypophosphorylation of phospholamban (PLN), 2 hyperphosphorylation of ryanodine receptor (RyR) 3 or a combination of both in failing cardiomyocytes. It has been increasingly recognized that dysregulation of protein phosphatase 1 (PP1) signaling is associated with the imbalance of kinase/phosphatase in the failing heart. 3,4 Therefore, PP1 inhibition has been thought of as a potential molecular target for restoring impaired Ca 2+ cycling mediated by the sarcoplasmic reticulum (SR). 4 In this regard, the role of inhibitor-1 (I-1), an endogenous PP1 inhibitor, has been drawing attention, not only for understanding the mechanism of increased PP1 activity in failing hearts, but also for its application as a potential therapeutic target. 5 Article p 1133I-1 is a ubiquitously expressed acid-and heat-stable cytosolic protein that is primarily rich in skeletal and cardiac muscle. 6 When I-1's Thr35 residue is phosphorylated by protein kinase A (PKA), I-1 actively inhibits PP1 activity, potentiates PKA phosphorylation, and enhances cardiac contractility. On the other hand, when the Ser67 or Thr75 residues are phosphorylated by protein kinase C α (PKAα) 7,8 or the Thr35 residue is dephosphorylated by PP2B, 9 I-1 becomes inactive, resulting in an increase in PP1 activity and suppression of cardiac contractility. Therefore, I-1 is also recognized as an important element of β-adrenergic signaling, as well as Gq-receptor coupled signaling (angiotensin II, endothelin, and α-adrenergic signaling). 10 It has been reported that in heart failure, phosphorylation of I-1 at Thr35 is reduced compared with normal hearts, 9 and its protein expression level is significantly decreased, 11 thereby contributing to impaired β-adrenergic signaling and hence cardiac dysfunction in heart failure.In this issue, Kawashima et al 12 report a specific effect of I-1 on the SR Ca 2+ cycling in normal saponin-permeabilized rat cardiomyocytes. They found that administration of I-1 significantly potentiated PKA-mediated SR Ca 2+ load without affecting Ca 2+ release function, as assessed by caffeine-induced Ca 2+ transient and Ca 2+ spark frequency. The effects of I-1 on SR Ca 2+ load and Ca 2+ release function were also characterized as similar to nonspecific chemical inhibition of protein phosphatase by calyculin A. Indeed, there are at least 2 possible mechanisms by which Ca 2+ spark frequency increased in the permeabilized cardiomyocytes; namely, an increased gating property of the RyR, increased SR Ca 2+ loading (SR Ca 2+ content) or a combination of both. SR Ca 2+ loading seems to be a more important target for I-1 than Ca 2+ release, because I-1 had no appreciable effect on Ca 2+ spark frequency and caffeine-induced Ca 2+ transient after an abrupt inhibition of the SR Ca 2+ uptake by cyc...