Abnormal Interactions of Calsequestrin With the Ryanodine Receptor Calcium Release Channel Complex Linked to Exercise-Induced Sudden Cardiac Death

Abstract

Abstract-Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic disorder associated with mutations in the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2) genes. Previous in vitro studies suggested that RyR2 and CASQ2 interact as parts of a multimolecular Ca 2ϩ -signaling complex; however, direct evidence for such interactions and their potential significance to myocardial function remain to be determined. We identified a novel CASQ2 mutation in a young female with a structurally normal heart and unexplained syncopal episodes. This mutation results in the nonconservative substitution of glutamine for arginine at amino acid 33 of CASQ2 (R33Q). Adenoviral-mediated expression of CASQ2 R33Q in adult rat myocytes led to an increase in excitationcontraction coupling gain and to more frequent occurrences of spontaneous propagating (

Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin‐Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia

“…Considering CaM binding to the cytosolic surface of RyR2 has been reported to contribute to inactivation of RyR2,17, 18, 19, 20 we tested whether arrhythmogenic mutations of CaM also act by shortening RyR2 refractoriness. Ca imaging was performed in permeabilized cardiac myocytes (cytosolic Ca buffered at 120 nmol/L) supplemented with different CaM protein variants 34, 35. Consistent with previous studies,31 the addition of the CPVT CaM N98S (100 nmol/L), to permeabilized myocytes isolated from WT mice significantly increased the frequency of Ca waves (as compared with WT CaM; Figure 1A and 1C).…”

IP3 Receptors: Toward Understanding Their Activation

“…Persuasive evidence suggests that Ca 2þ release by RyR may be terminated before Ca 2þ stores are entirely depleted because luminal Ca 2þ is required to maintain RyR activity (Györke and Györke 1998;Launikonis et al 2006;Jiang et al 2008), possibly via its interaction with calsequestrin, a luminal high-capacity Ca 2þ -binding protein (Launikonis et al 2006;Terentyev et al 2006). A similar scheme has been proposed to account for two features of IP 3 -evoked Ca 2þ release: the initiation of Ca 2þ release after the quiescent interspike interval during repetitive Ca 2þ spikes (Berridge 2007) and quantal Ca 2þ release via IP 3 R. The latter describes the situation wherein unidirectional Ca 2þ efflux from intracellular stores terminates before the stores have fully emptied after stimulation with submaximally effective concentrations of IP 3 without loss of their ability to respond to a further increase in IP 3 concentration (Muallem et al 1989;Meyer and Stryer 1990;Taylor and Potter 1990;Oldershaw et al 1991;Bootman et al 1992;Brown et al 1992;Combettes et al 1992;Ferris et al 1992;Hirota et al 1995).…”

Unfolded Protein Response Is Activated in the Hearts of Catecholaminergic Polymorphic Ventricular Tachycardia (Cpvt) Mice

“…Four of them are non-sense mutations that generate premature stop codons, while the other four are point mutations (15)(16)(17). The unique characteristic of each mutation can alter the clinical phenotype of the disease (18).…”