Histidine-rich calcium binding protein: The new regulator of sarcoplasmic reticulum calcium cycling

Abstract

The histidine-rich calcium binding protein (HRC) is a novel regulator of sarcoplasmic reticulum (SR) Ca 2+ -uptake, storage and release. Residing in the SR lumen, HRC binds Ca 2+ with high capacity but low affinity. In vitro phosphorylation of HRC affects ryanodine affinity of the ryanodine receptor (RyR), suggesting a functional role of HRC on SR Ca 2+ -release. Indeed, acute HRC overexpression in isolated rodent cardiomyocytes decreases Ca 2+ -induced Ca 2+ -release, increases SR Ca 2+ -load, and impairs contractility. The HRC effects on RyR may be regulated by the Ca 2+ -sensitivity of its interaction with triadin. However, HRC also affects the SR Ca 2+ -ATPase, as shown by HRC overexpression in transgenic mouse hearts, which resulted in reduced SR Ca 2+ -uptake rates, cardiac remodeling and hypertrophy. In fact, in vitro generated evidence suggests that HRC directly interacts with SR Ca 2+ -ATPase2, supporting a dual role of HRC in Ca 2+ -homeostasis: regulation of both SR Ca 2+ -uptake and Ca 2+ -release. Furthermore, HRC plays an important role in myocyte differentiation and in antiapoptotic cardioprotection against ischemia/reperfusion induced cardiac injury. Interestingly, HRC has been linked with familiar cardiac conduction disease and an HRC polymorphism was shown to associate with malignant ventricular arrhythmias in the background of idiopathic dilated cardiomyopathy. This review summarizes studies, which have established the critical role of HRC in Ca 2+ -homeostasis, suggesting its importance in cardiac physiology and pathophysiology.

The histidine-rich calcium binding protein (HRC) promotes tumor metastasis in hepatocellular carcinoma and is upregulated by SATB1

“…It regulates sarcoplasmic reticulum (SR) Ca 2+ -uptake, storage and release through calcium pumps and calcium channels [7, 8]. To examine the underlying mechanism of the increased [Ca 2+ ] i induced by HRC in HCC cells, we detected the expression of SERCA2, ryanodine receptor (RyR) and NCX.…”

“…Previous investigations demonstrated that the histidine-rich Ca 2+ -binding protein (HRC) is located in the lumen of the sarcoplasmic reticulum (SR) in heart, which functioned as a new regulator of SR Ca 2+ -homeostasis [7]. Since the discovery of HRC, related studies were all focused on heart diseases.…”

Phosphorylation of serine96 of histidine-rich calcium-binding protein by the Fam20C kinase functions to prevent cardiac arrhythmia

“…Other proteins also contribute to this process, including triadin and junctin, which regulate RYR2, and phospholamban, which regulates SERCA2a (4, 5). In the past decade, the histidine-rich Ca-binding protein (HRC) has been suggested to be an additional component of the SR Ca handling machinery (6). HRC is a regulator of both SERCA2a, through its direct binding interaction, and RyR2 function, through its binding to triadin.…”

“…HRC is a regulator of both SERCA2a, through its direct binding interaction, and RyR2 function, through its binding to triadin. HRC therefore mediates SR Ca storage, uptake, and release (6).…”

A conceptual paradigm of heart failure and systems biology approach

“…Overexpression of a constitutively active inhibitor-1 (I-1c) has beneficial effects on cardiac apoptosis and heart failure progression induced by prolonged beta-adrenergic stimulation [32]. The PRN is also regulated by Heat Shock Protein 20 (Hsp20) and Histidine Rich Calcium Binding protein (HRC) [33,34]. The Hsp20 increases phosphorylation of PLN and sarcoplasmic reticulum calcium cycling, maintains myocyte functioning, and increases cell survival.…”