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

The histidine-rich calcium binding protein (HRC) is a novel regulator of sarcoplasmic reticulum (SR) Ca²⁺-uptake, storage and release. Residing in the SR lumen, HRC binds Ca²⁺ 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 Ca²⁺-release. Indeed, acute HRC overexpression in isolated rodent cardiomyocytes decreases Ca²⁺-induced Ca²⁺-release, increases SR Ca²⁺-load, and impairs contractility. The HRC effects on RyR may be regulated by the Ca²⁺-sensitivity of its interaction with triadin. However, HRC also affects the SR Ca²⁺-ATPase, as shown by HRC overexpression in transgenic mouse hearts, which resulted in reduced SR Ca²⁺-uptake rates, cardiac remodeling and hypertrophy. In fact, in vitro generated evidence suggests that HRC directly interacts with SR Ca²⁺-ATPase2, supporting a dual role of HRC in Ca²⁺-homeostasis: regulation of both SR Ca²⁺-uptake and Ca²⁺-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 Ca²⁺-homeostasis, suggesting its importance in cardiac physiology and pathophysiology.