This study explains that the Calsequestrins (Casqs), comprising the Casq1 and Casq2 isoforms, buffer Ca2+ and regulate its release in the sarcoplasmic reticulum (SR) of skeletal and cardiac muscle, respectively. Human inherited diseases associated with mutations in CASQ1 or CASQ2 include malignant hyperthermia/environmental heat stroke (MH/EHS) and catecholaminergic polymorphic ventricular tachycardia. However, patients with an MH/EHS event often suffer from arrhythmia for which the underlying mechanism remains unknown.
Working hearts from conventional (Casq1-KO) and cardiac-specific (Casq1-CKO) Casq1 knockout mice were monitored in vivo and ex vivo by electrocardiogram and electrical mapping, respectively. MH was induced by 2% isoflurane and treated intraperitoneally with dantrolene. Time-lapse imaging was used to monitor intracellular Ca2+ activity in isolated mouse cardiomyocytes or neonatal rat ventricular myocytes (NRVMs) with knockdown, over-expression or truncation of the Casq1 gene. Conformational change in both Casqs was determined by crosslinking Western blot analysis.
Like MH/EHS patients, Casq1-KO and Casq1-CKO mice had faster basal heart rate, and ventricular tachycardia upon exposure to 2% isoflurane, which could be relieved by dantrolene. Basal sinus tachycardia and ventricular ectopic electrical triggering also occurred in Casq1-KO hearts ex vivo.
Reference link- https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.121.053255
