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(Circulation Research. 2007;101:617.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Modest Reductions of Cardiac Calsequestrin Increase Sarcoplasmic Reticulum Ca²⁺ Leak Independent of Luminal Ca²⁺ and Trigger Ventricular Arrhythmias in Mice

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

From the Oates Institute for Experimental Therapeutics and Division of Clinical Pharmacology, Departments of Medicine and Pharmacology (N.C., T.Y., I.H., B.C.K.); and Department of Pediatrics (P.J.K.), Vanderbilt University Medical Center, Nashville, Tenn; Cardiovascular Research Institute (T.H.), Washington Hospital Center, Washington DC; Laboratory for Mammalian Genes and Development (K.E., K.P.), National Institute of Child Health and Human Development/NIH, Bethesda, Md; Department of Medicine (B.A., L.R.J.), Krannert Institute of Cardiology, Indianapolis, Ind; and Department of Cell and Developmental Biology (C.F.-A.), University of Pennsylvania, Philadelphia.

Correspondence to Björn C. Knollmann, MD, PhD, Associate Professor of Medicine and Pharmacology, Oates Institute for Experimental Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, 1265 Medical Research Building IV, Nashville, TN 37232-0575. E-mail bjorn.knollmann{at}vanderbilt.edu

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⁺.

Key Words: calsequestrin • ventricular arrhythmia • SR Ca²⁺ leak • SR free luminal Ca²⁺ • catecholaminergic polymorphic ventricular tachycardia

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Linking Calsequestrin to Lumenal Control of SR Ca²⁺ Release

Thomas R. Shannon
Circ. Res. 2007 101: 539-541. [Full Text] [PDF]

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