Unfolded Protein Response Is Activated in the Hearts of Catecholaminergic Polymorphic Ventricular Tachycardia (Cpvt) Mice

Isoform 2 of calsequestrin (CSQ2) is the main calciumbinding protein of the sarcoplasmic reticulum (SR) and is expressed in both cardiac and skeletal muscle. CSQ2 acts as an SR calcium (Ca2+) sensor and regulates SR Ca 2+ release via interactions with triadin, junctin, and the ryanodine receptor. Various mutations of the csq2 gene lead to altered Ca 2+ release and contractile dysfunction and contribute to the development of arrhythmias and sudden cardiac death in young individuals affected by CPVT . Transgenic mice carrying one of the identified CSQ2 point mutations (R33Q) associated with CPVT were developed, and a drastic reduction in the mutated protein was observed. Following a biomolecular approach, several analyses were performed using different antibody treatments to identify when the reduction of CSQ2 begins, to unveil the mechanism involved in the reduction of CSQ2 and to verify whether other proteins are affected by the presence of the mutated protein. Th e results of this study showed that mutated CSQ2 levels decreased soon after birth, in conjunction with decreased levels of other important junctional SR proteins, including triadin (TD). Th e up-regulation of proteins associated with the unfolded protein response (UPR) was also observed, and the ATF6- dependent pathway was activated by the UPR. The presence of the R33Q mutation induced the decrease of CSQ2 via UPR activation and subsequent proteasomal degradation.