Regulatory roles of junctin in sarcoplasmic reticulum calcium cycling and myocardial function

Abstract

Junctin (JCN), a 26-kd sarcoplasmic reticulum (SR) transmembrane protein, forms a quaternary protein complex with the ryanodine receptor, calsequestrin, and triadin in the SR lumen of cardiac muscle. Within this complex, calsequestrin, triadin, and JCN appear to be critical for normal regulation of ryanodine receptor-mediated calcium (Ca) release. Junctin and triadin exhibit 60% to 70% amino acid homology in their transmembrane domains, including repeated KEKE motifs important for macromolecular protein-protein interactions within their SR luminal tails. Recent studies have uncovered functional roles of both JCN and triadin in the mouse heart, using transgenic overexpression strategies, which exhibit varying phenotypes including mild SR structural alterations, prolongation of Ca transient decay, impaired relaxation, and cardiac hypertrophy and/or heart failure. More specifically, both in vitro adenoviral gene transfer and in vivo gene-targeting techniques to manipulate JCN expression levels have shown that JCN is an essential factor in maintaining normal cardiac Ca handling and cardiac function. This article reviews the new findings on the regulatory roles of JCN in cardiac SR Ca cycling and contractility, with special emphasis on the effects of JCN ablation on delayed after depolarization-induced arrhythmias and premature mortality in mouse models.

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.