title: Calsequestrin 2 deletion shortens the refractoriness of Ca²⁺ release and reduces rate-dependent Ca²⁺-alternans in intact mouse hearts.
abstract: Calsequestrin (Casq2) is a low affinity Ca(2+)-binding protein located in sarcoplasmic reticulum (SR) of cardiac myocytes. Casq2 acts as a Ca(2+) buffer regulating free Ca(2+) concentration in the SR lumen and plays a significant role in the regulation of Ca(2+) release from this intracellular organelle. In addition, there is experimental evidence supporting the hypothesis that Casq2 also modulates the activity of the cardiac Ca(2+) release channels, ryanodine receptors (RyR2). In this study, Casq2 knockout mice (Casq2-/-) were used as a model to evaluate the effects of the Casq2 on the cytosolic and intra-SR Ca(2+) dynamics, and the electrical activity in the ventricular epicardial layer of intact beating hearts. Casq2-/- mice have accelerated intra-SR Ca(2+) refilling kinetics (76 ± 22 vs. 136.5 ± 15 ms) and a reduced refractoriness of Ca(2+) release (182 ± 32 ms Casq2+/+ and 111 ± 22 ms Casq2-/- ). In addition, mice display reduced Ca(2+) alternans (67% decline in the amplitude of Ca(2+) alternans at 7 Hz, 21oC) and less T-wave alternans at the electrocardiographic level. The results presented in this paper support the idea of Casq2 acting both as a buffer and a direct regulator of the Ca(2+) release process. Finally, we propose that alterations in Ca(2+) release refractoriness shown here could explain the relationship between Casq2 function and an increase in the risk for ventricular arrhythmias.
authors: School of Engineering, University of California Merced, Merced, CA, USA.
authors: Dmytro
authors: D
authors: Kornyeyev
authors: Azade D
authors: AD
authors: Petrosky
authors: Bernardo
authors: B
authors: Zepeda
authors: Marcela
authors: M
authors: Ferreiro
authors: Bjorn
authors: B
authors: Knollmann
authors: Ariel L
authors: AL
authors: Escobar
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002155:Calsequestrin / Q000235:genetics*; D003600:Cytosol / Q000378:metabolism; D055786:Gene Knockout Techniques; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D010496:Pericardium / Q000378:metabolism; D012032:Refractory Period, Electrophysiological; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000378:metabolism
chemical_list: D002155:Calsequestrin; C514388:casq2 protein, mouse; D002118:Calcium