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

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

doi:10.1172/jci29128

Cited by 314 publications

(579 citation statements)

References 55 publications

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“…Knollmann and coworkers showed that Casq2-null mice are viable and display normal SR Ca 2þ release and contractile function under basal conditions. However, exposure to catecholamines in Casq2-null myocytes caused increased diastolic SR Ca 2þ leak, resulting in premature spontaneous SR Ca 2þ releases that triggered beats indicating that these mice are susceptible to catecholaminergic ventricular arrhythmias (Knollmann et al 2006). FKBPs are named according to their molecular mass and belong to the immunophilins, a family of highly conserved proteins that bind immunosuppressive drugs such as FK506 and rapamycin.…”

Section: Calsequestrinmentioning

confidence: 99%

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Lanner¹,

Georgiou²,

Joshi³

et al. 2010

Cold Spring Harbor Perspectives in Biology

677

572

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Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca 2þ from intracellular stores during excitation-contraction coupling in both cardiac and skeletal muscle. RyRs are the largest known ion channels (.2MDa) and exist as three mammalian isoforms (RyR 1 -3), all of which are homotetrameric proteins that interact with and are regulated by phosphorylation, redox modifications, and a variety of small proteins and ions. Most RyR channel modulators interact with the large cytoplasmic domain whereas the carboxy-terminal portion of the protein forms the ion-conducting pore. Mutations in RyR2 are associated with human disorders such as catecholaminergic polymorphic ventricular tachycardia whereas mutations in RyR1 underlie diseases such as central core disease and malignant hyperthermia. This chapter examines the current concepts of the structure, function and regulation of RyRs and assesses the current state of understanding of their roles in associated disorders.

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Section: Calsequestrinmentioning

confidence: 99%

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Lanner¹,

Georgiou²,

Joshi³

et al. 2010

Cold Spring Harbor Perspectives in Biology

677

572

View full text Add to dashboard Cite

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“…Ventricular myocytes from 12-to 16-week-old mice (C57BL/6 strain) were isolated using modified collagenase/protease method, as previously described [16]. All chemicals, unless otherwise specified, were obtained from Sigma (St. Louis, MO).…”

Section: Myocyte Isolation and Ca 2+ Indicator Loadingmentioning

confidence: 99%

In Vitro Studies Indicate Intravenous Lipid Emulsion Acts as Lipid Sink in Verapamil Poisoning

et al. 2015

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Intravenous lipid emulsion (ILE), a component of parenteral nutrition, consists of a fat emulsion of soy bean oil, egg phospholipids, and glycerin. Case reports suggest that ILE may reverse hypotension caused by acute poisoning with lipophilic drugs such as verapamil, but the mechanism remains unclear. The methods used are the following: (1) measurement of ILE concentration in serum samples from a patient with verapamil poisoning treated with ILE, (2) measurement of free verapamil concentrations in human serum mixed in vitro with increasing concentrations of ILE, and (3) measurement of murine ventricular cardiomyocyte L-type Ca 2+ currents, intracellular Ca 2+ , and contractility in response to verapamil and/or ILE. Maximum patient serum ILE concentration after infusion of 1 L ILE over 1 h was approximately 1.6 vol%. In vitro GC/ MS verapamil assays showed that addition of ILE (0.03-5.0 vol%) dose-dependently decreased the free verapamil concentration in human serum. In voltage-clamped myocytes, adding ILE to Tyrode's solution containing 5 μM verapamil recovered L-type Ca 2+ currents (I Ca ). Recovery was concentration dependent, with significant I Ca recovery at ILE concentrations as low as 0.03 vol%. ILE had no effect on I Ca in the absence of verapamil. In field-stimulated intact ventricular myocytes exposed to verapamil, adding ILE (0.5 %) resulted in a rapid and nearly complete recovery of myocyte contractility and intracellular Ca 2+ . Our in vitro studies indicate that ILE acts as a lipid sink that rapidly reverses impaired cardiomyocyte contractility in the continued presence of verapamil.

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“…Cardiomyocytes were inoculated in 35 mm dishes (MatTeK Corporation, USA) and loaded with 5 μM fluo-3 AM (Sigma Chemical Co., USA). Intracellular fluo-3 AM was excited by a DG-4 quartz lamp filtered at 488 nm, and emission wavelengths were monitored with a 520 nm long-pass filter in 37 °C perfusion solution (in mM: 145 NaCl, 5.4 KCl, 0.5 MgCl 2 , 1.2 CaCl 2 , 5 HEPES, 5.5 Glucose, 0.3 NaH 2 PO 4 , pH 7.4) [20]. Rapid scanning of the observation field (5 s/scan) was used to minimize photo-oxidation artifacts.…”

Section: 25mentioning

confidence: 99%

Sarcoplasmic reticulum Ca2+ release channel ryanodine receptor (RyR2) plays a crucial role in aconitine-induced arrhythmias

Fu¹,

Li²,

Fan³

et al. 2008

Biochemical Pharmacology

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The present study established a model of RyR 2 knockdown cardiomyocytes and elucidated the role of RyR 2 in aconitine-induced arrhythmia. Cardiomyocytes were obtained from hearts of neonatal Sprague-Dawlay rats. siRNAs were used to down-regulate RyR 2 expression. Reduction of RyR 2 expression was documented by RT-PCR, western blot, and immunofluorescence. Ca 2+ signals were investigated by measuring the relative intracellular Ca 2+ concentration, spontaneous Ca 2+ oscillations, caffeine-induced Ca 2+ release, and L-type Ca 2+ currents. In normal cardiomyocytes, steady and periodic spontaneous Ca 2+ oscillations were observed, and the baseline [Ca 2+ ] i remained at the low level. Exposure to 3 μM aconitine increased the frequency and decreased the amplitude of Ca 2+ oscillations; the baseline [Ca 2+ ] i and the level of caffeineinduced Ca 2+ release were increased but the L-type Ca 2+ currents were inhibited after application of 3 μM aconitine for 5 min. In RyR 2 knockdown cardiomyocytes, the steady and periodic spontaneous Ca 2+ oscillations almost disappeared, but were re-induced by aconitine without affecting the baseline [Ca 2+ ] i level; the level of caffeine-induced Ca 2+ release was increased but L-type Ca 2+ currents were inhibited. Alterations of RyR 2 are important consequences of aconitinestimulation and activation of RyR 2 appear to have a direct relationship with aconitine-induced arrhythmias. The present study demonstrates a potential method for preventing aconitine-induced arrhythmias by inhibiting Ca 2+ leakage through the sarcoplasmic reticulum RyR 2 channel.

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

Cited by 314 publications

References 55 publications

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

In Vitro Studies Indicate Intravenous Lipid Emulsion Acts as Lipid Sink in Verapamil Poisoning

Sarcoplasmic reticulum Ca2+ release channel ryanodine receptor (RyR2) plays a crucial role in aconitine-induced arrhythmias

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