Calsequestrin 2 deletion shortens the refractoriness of Ca²⁺ release and reduces rate-dependent Ca²⁺-alternans in intact mouse hearts

J Mol Cell Cardiol. 2012 Jan;52(1):21-31. doi: 10.1016/j.yjmcc.2011.09.020. Epub 2011 Sep 29.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Signaling
  • Calsequestrin / genetics*
  • Cytosol / metabolism
  • Gene Knockout Techniques
  • Mice
  • Mice, Knockout
  • Myocardial Contraction / genetics
  • Myocardium / metabolism*
  • Pericardium / metabolism
  • Refractory Period, Electrophysiological*
  • Sarcoplasmic Reticulum / genetics
  • Sarcoplasmic Reticulum / metabolism


  • Calsequestrin
  • casq2 protein, mouse
  • Calcium