To B-E3 or Not to B-E3

erturbations in myocardial Ca 2+ signaling have long been considered key to the pathology of many cardiovascular diseases, including pressure overload hypertrophy, dilated cardiomyopathy, and ischemic heart disease.These diseases involve significant remodeling of the transverse (T)-tubule network, inducing the transition from a highly organized structure to a disordered state characterized by T-tubule dilatation, rarefaction, and dissociation of the T-tubule from the junctional sarcoplasmic reticulum (jSR). 1 Such changes create areas where the L-type Ca 2+ channel is no longer in close proximity to the ryanodine receptor (RyR2) in the dyad, resulting in dyssynchronous Ca 2+ release from the RyR2, reduced inotropic reserve, and increased risk of delayed afterdepolarizations and resultant arrhythmias.Under physiological conditions, junctophilin-2 (JP2) plays a key role in maintaining structural integrity by stabilizing the T-tubules and anchoring them to the jSR, thereby facilitating effective Ca 2+ -induced Ca 2+ release.Ca 2+ release is also regulated by the jSR Ca 2+ release unit, composed of RyR2, Junctin (JCN), Triadin, and Calsequestrin, which together regulate RyR2 gating and RyR2-mediated Ca 2+ release (Figure 1).Loss-offunction mutations in JP2 and reductions in JP2 and JCN expression are evident in human and animal models of heart failure and cardiac stress, and result in perturbations in Ca 2+ handling. 1,2Conversely, studies showing an increase or overexpression of JP2, either as its full-length form or an N-terminal fragment, preserve Ca 2+ handling and are protective in models of heart failure. 3,4Collectively, these studies highlight a beneficial role in preserving the expression of JP2 and JCN for the maintenance of cardiac contractility during periods of stress and increased workload.