Ablation of HRC alleviates cardiac arrhythmia and improves abnormal Ca handling in CASQ2 knockout mice prone to CPVT

Cardiovasc Res. 2015 Nov 1;108(2):299-311. doi: 10.1093/cvr/cvv222. Epub 2015 Sep 25.


Aims: Cardiac calsequestrin (CASQ2) and histidine-rich Ca-binding protein (HRC) are sarcoplasmic reticulum (SR) Ca-binding proteins that regulate SR Ca release in mammalian heart. Deletion of either CASQ2 or HRC results in relatively mild phenotypes characterized by preserved cardiac structure and function, although CASQ2 knockout (KO), or Cnull, shows increased arrhythmia burden under conditions of catecholaminergic stress. We hypothesized that given the apparent overlap of functions of CASQ2 and HRC, simultaneous ablation of both would deteriorate the cardiac phenotype compared with the single knockouts.

Methods and results: In contrast to this expectation, double knockout (DKO) mice lacking both CASQ2 and HRC exhibited normal cardiac ejection fraction and ultrastructure. Moreover, the predisposition to catecholamine-dependent arrhythmia that characterizes the Cnull phenotype was alleviated in the DKO mice. At the myocyte level, DKO mice displayed Ca transients of normal amplitude; additionally, the frequency of spontaneous Ca waves and sparks in the presence of isoproterenol were decreased markedly compared with Cnull. Furthermore, restitution of SR Ca release was slowed in DKO myocytes compared with Cnull cells.

Conclusion: Our results suggest that rather than being functionally redundant, CASQ2 and HRC modulate cardiac ryanodine receptor-mediated (RyR2) Ca release in an opposing manner. In particular, while CASQ2 stabilizes RyR2 rendering it refractory in the diastolic phase, HRC enhances RyR2 activity facilitating RyR2 recovery from refractoriness.

Keywords: Catecholaminergic polymorphic ventricular tachycardia; Excitation–contraction coupling; Ryanodine receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Calsequestrin / genetics
  • Calsequestrin / metabolism*
  • Disease Models, Animal
  • Echocardiography
  • Isoproterenol
  • Mice, Knockout
  • Myocardial Contraction
  • Myocytes, Cardiac / metabolism
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Tachycardia, Ventricular / metabolism*


  • Calcium-Binding Proteins
  • Calsequestrin
  • Hrc protein, mouse
  • Ryanodine Receptor Calcium Release Channel
  • casq2 protein, mouse
  • ryanodine receptor 2. mouse
  • Isoproterenol
  • Calcium

Supplementary concepts

  • Polymorphic catecholergic ventricular tachycardia