Abstract 1399: Cardiac Calsequestrin Deletion Causes Premature Sarcoplasmic Reticulum Calcium Release and Catecholaminergic Polymorphic Ventricular Tachycardia in Mice
Cardiac calsequestrin (Casq2) is thought to be the key sarcoplasmic reticulum (SR) Ca2+-storage protein essential for SR Ca2+- release in mammalian heart. In humans, CASQ2 mutations cause a syndrome of catecholaminergic polymorphic ventricular tachycardia (CPVT) and sudden cardiac death. To determine the mechanisms whereby CASQ2 mutations cause electrophysiological instability, we generated Casq2 null (Casq2−/−) mice. Here we show that Casq2−/− mice phenocopy the resting bradycardia and CPVT of human carriers of CASQ2 mutations. Compared to Casq2+/+ mice (n=16), Casq2−/− mice (n=11) displayed a significantly increased incidence of premature ventricular beats (PVBs: 38% vs. 91%, p<0.01) and VT after exposure to isoproterenol and developed bidirectional VT (Figure⇓, s denotes sinus beats) after treadmill exercise (0% vs. 100%, n=4 each, p<0.05). Beta-adrenergic stimulation caused premature spontaneous SR Ca2+- releases and triggered beats in a much larger fraction of Casq2−/− than Casq2+/+ myocytes (60% vs. 15%, n=43 and 27, p<0.001). Application of caffeine, which opens ryanodine receptor channels and empties the SR, abolished the spontaneous Ca2+ transients. Voltage-clamped Casq2−/− myocytes displayed transient inward currents (Iti) responsible for delayed afterdepolarization, which could be prevented by NaCa exchanger inhibition with LiCl.
Conclusion: Casq2 likely functions as a “molecular safety switch” that prevents premature spontaneous SR Ca2+ releases and thereby maintains an orderly heart rhythm during adrenergic stimulation, such as the “fight or flight” response.