Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia

Björn C. Knollmann, Nagesh Chopra, Thinn Hlaing, Brandy Akin, Tao Yang, Kristen Ettensohn, Barbara E.C. Knollmann, Kenneth D. Horton, Neil J. Weissman, Izabela Holinstat, Wei Zhang, Dan M. Roden, Larry R. Jones, Clara Franzini-Armstrong, Karl Pfeifer

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309 Scopus citations

Abstract

Cardiac calsequestrin (Casq2) is thought to be the key sarcoplasmic reticulum (SR) Ca2+ storage protein essential for SR Ca2+ release in mammalian heart. Human CASQ2 mutations are associated with catecholaminergic ventricular tachycardia. However, homozygous mutation carriers presumably lacking functional Casq2 display surprisingly normal cardiac contractility. Here we show that Casq2-null mice are viable and display normal SR Ca2+ release and contractile function under basal conditions. The mice exhibited striking increases in SR volume and near absence of the Casq2-binding proteins triadin-1 and junctin; upregulation of other Ca 2+-binding proteins was not apparent. Exposure to catecholamines in Casq2-null myocytes caused increased diastolic SR Ca2+ leak, resulting in premature spontaneous SR Ca2+ releases and triggered beats. In vivo, Casq2-null mice phenocopied the human arrhythmias. Thus, while the unique molecular and anatomic adaptive response to Casq2 deletion maintains functional SR Ca2+ storage, lack of Casq2 also causes increased diastolic SR Ca2+ leak, rendering Casq2-null mice susceptible to catecholaminergic ventricular arrhythmias.

Original languageEnglish (US)
Pages (from-to)2510-2520
Number of pages11
JournalJournal of Clinical Investigation
Volume116
Issue number9
DOIs
StatePublished - Sep 1 2006

ASJC Scopus subject areas

  • Medicine(all)

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    Knollmann, B. C., Chopra, N., Hlaing, T., Akin, B., Yang, T., Ettensohn, K., Knollmann, B. E. C., Horton, K. D., Weissman, N. J., Holinstat, I., Zhang, W., Roden, D. M., Jones, L. R., Franzini-Armstrong, C., & Pfeifer, K. (2006). Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia. Journal of Clinical Investigation, 116(9), 2510-2520. https://doi.org/10.1172/JCI29128