Junctin

Junctin (JCN) is a 26-kDa integral membrane protein, which forms a quaternary protein complex with the ryanodine receptor, calsequestrin and triadin at the junctional sarcoplasmic reticulum (SR) membrane in cardiac and skeletal muscles. Our recent studies indicate that adenovirus-mediated acute decrease in JCN levels resulted in enhanced contractile parameters, SR Ca transient peak, and Ca kinetics, whereas overexpression of JCN had opposite effects in isolated cardiomyocytes. Similarly, ablation of JCN in vivo was associated with enhanced cardiac contractility and SR Ca kinetics in intact animals and in single isolated myocytes. However, ablation of JCN resulted in SR Ca overload, which further triggered arrhythmias and predisposed to sudden cardiac death. The explanation is that the suprathreshold levels of SR Ca load, coupled with dysregulation of RyR by SR luminal Ca, enhanced the spontaneous RyR openings, which eventually trigger arrhythmias through activation of DADs (Figure 1).

Figure 1. The mechanism of cardiac arrhythmias in JCN knockout mice. Left panel, In the presence of JCN, the SR Ca leak is low because of the inhibition of RyR activity by JCN. The low level of Ca is mainly removed by SERCA2a, whereas Na-Ca exchanger is not involved; therefore, there is no inward current through Na-Ca exchanger to activate DAD and trigger arrhythmias. Right panel, Ablation of JCN causes (a) a dramatic increase in SR Ca load and (b) enhanced RyR activity, both of which can significantly increase RyR spontaneous Ca release (SR Ca leak). Under stress conditions, the SR Ca load is further increased to a suprathreshold level, which causes excessive spontaneous RyR Ca release (massive SR Ca leak). Cardiac SR Ca-adenosinetriphosphatase is not able to remove all the Ca into SR; thus, some of the Ca must be extruded by Na-Ca exchanger to maintain a normal cytosolic Ca concentration. Because the molar ratio of Na-Ca exchanger is 3Na:1Ca, an inward current is generated during extrusion of Ca, which may depolarize the cell membrane and induce extra cardiac contractions. NCX indicates Na-Ca exchanger; LTCC, L-type Ca channel; TRI, triadin.