Document Detail

Modest reductions of cardiac calsequestrin increase sarcoplasmic reticulum Ca2+ leak independent of luminal Ca2+ and trigger ventricular arrhythmias in mice.
MedLine Citation:
PMID:  17656677     Owner:  NLM     Status:  MEDLINE    
Cardiac calsequestrin-null mice (Casq2-/-) display catecholaminergic ventricular tachycardia akin to humans with CASQ2 mutations. However, the specific contribution of Casq2 deficiency to the arrhythmia phenotype is difficult to assess because Casq2-/- mice also show significant reductions in the sarcoplasmic reticulum (SR) proteins junctin and triadin-1 and increased SR volume. Furthermore, it remains unknown whether Casq2 regulates SR Ca2+ release directly or indirectly by buffering SR luminal Ca2+. To address both questions, we examined heterozygous (Casq2+/-) mice, which have a 25% reduction in Casq2 but no significant decrease in other SR proteins. Casq2+/- mice (n=35) challenged with isoproterenol displayed 3-fold higher rates of ventricular ectopy than Casq2+/+ mice (n=31; P<0.05). Programmed stimulation induced significantly more ventricular tachycardia in Casq2+/- mice than in Casq2+/+ mice. Field-stimulated Ca2+ transients, cell shortening, L-type Ca2+ current, and SR volume were not significantly different in Casq2+/- and Casq2+/+ myocytes. However, in the presence of isoproterenol, SR Ca2+ leak was significantly increased in Casq2+/- myocytes (Casq2+/- 0.18+/-0.02 F(ratio) versus Casq2+/+ 0.11+/-0.01 F(ratio), n=57, 60; P<0.01), resulting in a significantly higher rate of spontaneous SR Ca2+ releases and triggered beats. SR luminal Ca2+ measured using Mag-Fura-2 was not altered by Casq2 reduction. As a result, the relationship between SR Ca2+ leak and SR luminal Ca2+ was significantly different between Casq2+/- and Casq2+/+ myocytes (P<0.01). Thus, even modest reductions in Casq2 increase SR Ca2+ leak and cause ventricular tachycardia susceptibility under stress. The underlying mechanism is likely the direct regulation of SR Ca2+ release channels by Casq2 rather than altered luminal Ca2+.
Nagesh Chopra; Prince J Kannankeril; Tao Yang; Thinn Hlaing; Izabela Holinstat; Kristen Ettensohn; Karl Pfeifer; Brandy Akin; Larry R Jones; Clara Franzini-Armstrong; Björn C Knollmann
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2007-07-26
Journal Detail:
Title:  Circulation research     Volume:  101     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2007 Sep 
Date Detail:
Created Date:  2007-09-17     Completed Date:  2007-09-28     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  617-26     Citation Subset:  IM    
Oates Institute for Experimental Therapeutics, and Division of Clinical Pharmacology, Vanderbilt University Medical Center, 1265 Medical Research Building IV, Nashville, TN 37232-0575, USA.
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MeSH Terms
Calcium / metabolism
Calcium Channels / metabolism*
Calcium Signaling*
Calcium-Binding Protein, Vitamin D-Dependent / metabolism
Calsequestrin / deficiency,  genetics,  metabolism*
Cardiac Pacing, Artificial
Disease Models, Animal
Heart Rate
Ion Channel Gating*
Mice, Knockout
Mice, Transgenic
Myocardial Contraction
Myocytes, Cardiac / metabolism*,  ultrastructure
Sarcoplasmic Reticulum / metabolism*,  ultrastructure
Tachycardia, Ventricular / chemically induced,  genetics,  metabolism*,  pathology,  physiopathology
Time Factors
Ventricular Function
Ventricular Premature Complexes / chemically induced,  genetics,  metabolism*,  pathology,  physiopathology
Grant Support
Reg. No./Substance:
0/Calcium Channels; 0/Calcium-Binding Protein, Vitamin D-Dependent; 0/Calsequestrin; 0/calretinin; 0/casq2 protein, mouse; 7440-70-2/Calcium; 7683-59-2/Isoproterenol
Comment In:
Circ Res. 2007 Sep 14;101(6):539-41   [PMID:  17872471 ]

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