title: Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia.
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 Ca2+ -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.
authors.affiliation: Oates Institute for Experimental Therapeutics and Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0575, USA. bjorn.knollmann@vanderbilt.edu
authors.forename: Björn C
authors.initials: BC
authors.lastname: Knollmann
authors.forename: Nagesh
authors.initials: N
authors.lastname: Chopra
authors.forename: Thinn
authors.initials: T
authors.lastname: Hlaing
authors.forename: Brandy
authors.initials: B
authors.lastname: Akin
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Kristen
authors.initials: K
authors.lastname: Ettensohn
authors.forename: Barbara E C
authors.initials: BE
authors.lastname: Knollmann
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Horton
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Weissman
authors.forename: Izabela
authors.initials: I
authors.lastname: Holinstat
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Larry R
authors.initials: LR
authors.lastname: Jones
authors.forename: Clara
authors.initials: C
authors.lastname: Franzini-Armstrong
authors.forename: Karl
authors.initials: K
authors.lastname: Pfeifer
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002118:Calcium / Q000502:physiology*; D002155:Calsequestrin / Q000172:deficiency* / Q000235:genetics; D003433:Crosses, Genetic; D017931:DNA Primers; D003971:Diastole; D004562:Electrocardiography; D005091:Exons; D006321:Heart / Q000502:physiology; D006720:Homozygote; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D011110:Polymorphism, Genetic; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012519:Sarcoplasmic Reticulum / Q000502:physiology*; D017180:Tachycardia, Ventricular / Q000235:genetics*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002155:Calsequestrin; C506387:Cflar protein, mouse; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D012313:RNA; D002118:Calcium