The role of mutant protein level in autosomal recessive catecholamine dependent polymorphic ventricular tachycardia (CPVT2)

Biochem Pharmacol. 2013 Dec 1;86(11):1576-83. doi: 10.1016/j.bcp.2013.09.012. Epub 2013 Sep 23.


Humans and genetically engineered mice with recessively inherited CPVT develop arrhythmia which may arise due to malfunction or degradation of calsequestrin (CASQ2). We investigated the relation between protein level and arrhythmia severity in CASQ2(D307H/D307H) (D307H), compared to CASQ2(Δ/Δ) (KO) and wild type (WT) mice. CASQ2 expression and Ca²⁺ transients were recorded in cardiomyocytes from neonatal or adult mice. Arrhythmia was studied in vivo using heart rhythm telemetry at rest, exercise and after epinephrine injection. CASQ2 protein was absent in KO heart. Neonatal D307H and WT hearts expressed significantly less CASQ2 protein than the level found in the adult WT. Adult D307H expressed only 20% of CASQ2 protein found in WT. Spontaneous Ca²⁺ release was more prevalent in neonatal KO cardiomyocytes (89%) compared to 33-36% of either WT or D307H, respectively, p<0.001. Adult cardiomyocytes from both mutant mice had more Ca²⁺ abnormalities compared to control (KO: 82%, D307H 63%, WT 12%, p<0.01). Calcium oscillations were most common in KO cardiomyocytes. We then treated mice with bortezomib to inhibit CASQ2(D307H) degradation. Bortezomib increased CASQ2 expression in D307H hearts by ∼50% (p<0.05). Bortezomib-treated D307H mice had lower CPVT prevalence and less premature ventricular beats during peak exercise. No benefit against arrhythmia was observed in bortezomib treated KO mice. These results indicate that the mutant CASQ2(D307H) protein retains some of its physiological function. Its expression decreases with age and is inversely related to arrhythmia severity. Preventing the degradation of mutant protein should be explored as a possible therapeutic strategy in appropriate CPVT2 patients.

Keywords: Arrhythmia; Bortezomib; Calcium transients; Calsequestrin; Mouse model; Protein degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics*
  • Animals
  • Animals, Newborn
  • Boronic Acids / pharmacology
  • Bortezomib
  • Calcium / metabolism
  • Calsequestrin / biosynthesis
  • Calsequestrin / genetics*
  • Cells, Cultured
  • Gene Expression
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation*
  • Myocytes, Cardiac / metabolism
  • Pyrazines / pharmacology
  • Sarcoplasmic Reticulum / drug effects
  • Sarcoplasmic Reticulum / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Severity of Illness Index
  • Tachycardia, Ventricular / genetics*
  • Tachycardia, Ventricular / metabolism


  • Boronic Acids
  • Calsequestrin
  • Pyrazines
  • casq2 protein, mouse
  • Bortezomib
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium

Supplementary concepts

  • Polymorphic catecholergic ventricular tachycardia