Regulatory role of regucalcin in heart calcium signaling: Insight into cardiac failure (Review)

Abstract

Regucalcin was first identified in 1978 as a regulatory protein of Ca²⁺ signaling in liver cells. Regucalcin was shown to play a multifunctional role in cell regulation, such as maintainance of intracellular Ca²⁺ homeostasis and suppression of signal transduction, protein synthesis, nuclear function, cell proliferation and apoptosis in various types of cells and tissues. Cardiac excitation-contraction coupling is based on the regulation of intracellular Ca²⁺ concentration by the Ca²⁺ pump in the sarcoplasmic reticulum of heart muscle cells. Regucalcin, which is expressed in the heart, was found to increase rat heart sarcoplasmic reticulum Ca²⁺-ATPase activity and ATP-dependent Ca²⁺ uptake and mitochondrial Ca²⁺-ATPase activity. Regucalcin was also shown to suppress Ca²⁺-dependent protein tyrosine phosphatase, Ca²⁺/calmodulin-dependent protein phosphatase (calcineurin) and nitric oxide (NO) synthase activity in the heart cytoplasm. Moreover, regucalcin was found to activate superoxide dismutase (SOD), which plays a significant role in the prevention of cell death and apoptosis in the heart. Regucalcin may be a key molecule in heart muscle cell regulation through Ca²⁺ signaling. Regucalcin may also play a pathophysiological role in heart failure. The aim of this study was to review the recent findings regarding the role of regucalcin in Ca²⁺ signaling in the heart.

Keywords: Ca2+ signaling; Ca2+-ATPase; heart failure; nitric oxide synthase; regucalcin; sarcoplasmic reticulum Ca2+-ATPase; superoxide dismutase.

Figure 1

Role of regucalcin (RGN) in the regulation of heart cell Ca²⁺ signaling. Regucalcin is expressed in heart cells. Regucalcin stimulates Ca²⁺ uptake in the sarcoendoplasmic reticulum and mitochondria through activating the sarcoendoplasmic reticulum Ca²⁺-ATPase (SERCA2a) and the mitochondrial Ca²⁺-ATPase, which are Ca²⁺ pump enzymes maintaining intracellular Ca²⁺ homeostasis. Regucalcin suppresses Ca²⁺/calmodulin-dependent protein phosphatase and nitric oxide (NO) synthase activity and activates superoxide dismutase (SOD) in the heart cytoplasm. cAMP, cyclic AMP; PKA, protein kinase A; P, phosphorylation; RyR, ryanodine receptor; PLB, phospholanbane.