Junctin and the histidine-rich Ca2+ binding protein: potential roles in heart failure and arrhythmogenesis

Abstract

Contractile dysfunction and ventricular arrhythmias associated with heart failure have been attributed to aberrant sarcoplasmic reticulum (SR) Ca(2+) cycling. The study of junctin (JCN) and histidine-rich Ca(2+) binding protein (HRC) becomes of particular importance since these proteins have been shown to be critical regulators of Ca(2+) cycling. Specifically, JCN is a SR membrane protein, which is part of the SR Ca(2+) release quaternary structure that also includes the ryanodine receptor, triadin and calsequestrin. Functionally, JCN serves as a bridge between calsequestrin and the Ca(2+) release channel, ryanodine receptor. HRC is a SR luminal Ca(2+) binding protein known to associate with both triadin and the sarcoplasmic reticulum Ca(2+)-ATPase, and may thus mediate the crosstalk between SR Ca(2+) uptake and release. Indeed, evidence from genetic models of JCN and HRC indicate that they are important in cardiophysiology as alterations in these proteins affect SR Ca(2+) handling and cardiac function. In addition, downregulation of JCN and HRC may contribute to Ca(2+) cycling perturbations manifest in the failing heart, where their protein levels are significantly reduced. This review examines the roles of JCN and HRC in SR Ca(2+) cycling and their potential significance in heart failure.

Figure 2. Altered Ca²⁺ handling in junctin-null mice

A, representative traces of aftercontractions (signified by arrows) in WT and junctin KO myocytes at 5 Hz and 1 μmol l⁻¹ isoproterenol stimulation. B, representative traces of action potentials in WT and junctin KO myocytes at 5 Hz and isoproterenol stimulation. Delayed afterdepolarization is marked with arrows. Modified with permission from Yuan et al. 2007.

Figure 1. Cardiac arrhythmias in junctin-null mice

A, top, representative ECG recordings of WT mice after injection of isoproterenol (0.25 μg g⁻¹i.p.); bottom: ventricular tachycardia in junctin-KO mice after injection of isoproterenol (0.25 μg g⁻¹i.p.; n= 3). B, top, representative ECG tracings in WT mice after isoproterenol pump implantation; Middle and lower panels, premature ventricular contractions in 2 junctin-null mice during chronic isoproterenol stimulation. Modified with permission from Yuan et al. (2007).

Figure 3. Kaplan–Meier plots for the probability of survival of patients with idiopathic dilated cardiomyopathy according to HRC genotype

Kaplan–Meier plots of life-threatening ventricular arrhythmic events including sudden cardiac death and episodes of unstable VT (>180 b.p.m.) or ventricular fibrillation (A) and cardiac death from any cause, including pump failure, transplantation, sudden cardiac death, and episodes of unstable VT (>180 b.p.m.) or ventricular fibrillation (B). Arrhythmic events and cardiac death events were recorded by an implantable cardioverter-defibrillator device. Each trace signifies the HRC genotype at amino acid 96 for that patient group, and each event (life-threatening arrhythmia (A) or cardiac death (B)) is depicted as a step down. Each censored case (patient withdrawal due to other causes except sudden cardiac death, heart transplantation, and study termination (A) and death from non-cardiac etiology and study termination (B)) is marked with a cross. The table at the bottom of the plots indicates the number of dilated cardiomyopathy patients at risk for each year of follow-up study. The Ala/Ala homozygotes for the Ser96Ala polymorphism were statistically more susceptible to ventricular arrhythmic events, compared with Ser/Ala heterozygotes and Ser/Ser homozygotes. Modified from Arvanitis et al. 2008).

Figure 4. Proposed protein interactions in the SR lumen under low and high SR Ca²⁺

A, when the SR Ca²⁺ levels are low, maximal interaction may occur between HRC and SERCA thereby mediating the rate of SR Ca²⁺ uptake, while interaction between JCN and CSQ reduces Ca²⁺ leak through the RyR. B, when the SR Ca²⁺ content is high, HRC dissociates from SERCA and promotes interaction with triadin, which may simultaneously affect Ca²⁺ uptake and RyR activity. Junctin interaction with CSQ is reduced, possibly facilitating Ca²⁺ leak through the RyR.