Clinical Implications of Cardiac Ryanodine Receptor/Calcium Release Channel Mutations Linked to Sudden Cardiac Death

Marks, Andrew R.

doi:10.1161/01.cir.0000021746.82888.83

Cited by 33 publications

(19 citation statements)

References 36 publications

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“…2). This is in agreement with experimental findings (22,45) and the clinical manifestation of the disease condition seen in patients (17,26,36,39).…”

Section: Discussionsupporting

confidence: 92%

“…Recent work suggests that disruption of the RyR complex can lead to arrhythmogenic right ventricular dysplasia type 2 and catecholaminergic and familial polymorphic ventricular tachycardia (5,26,27,43). These lethal disruptions have been linked to genetic defects (13,17,27,37,43), transient pharmacological treatment (caffeine, tacrolimus) (3,4,31), or acquired diseases such as heart failure (49).…”

Section: Discussionmentioning

confidence: 99%

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Ryanodine receptor dysfunction and triggered activity in the heart

Katra¹,

Oya²,

Hoeker³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Katra RP, Oya T, Hoeker GS, Laurita KR. Ryanodine receptor dysfunction and triggered activity in the heart. Am J Physiol Heart Circ Physiol 292: H2144 -H2151, 2007. First published December 22, 2006; doi:10.1152/ajpheart.00924.2006.-Arrhythmogenesis has been increasingly linked to cardiac ryanodine receptor (RyR) dysfunction. However, the mechanistic relationship between abnormal RyR function and arrhythmogenesis in the heart is not clear. We hypothesize that, under abnormal RyR conditions, triggered activity will be caused by spontaneous calcium release (SCR) events that depend on transmural heterogeneities of calcium handling. We performed highresolution optical mapping of intracellular calcium and transmembrane potential in the canine left ventricular wedge preparation (n ϭ 28). Rapid pacing was used to initiate triggered activity under normal and abnormal RyR conditions induced by FKBP12.6 dissociation and ␤-adrenergic stimulation (20 -150 M rapamycin, 0.2 M isoproterenol). Under abnormal RyR conditions, almost all preparations experienced SCRs and triggered activity, in contrast to control, rapamycin, or isoproterenol conditions alone. Furthermore, under abnormal RyR conditions, complex arrhythmias (monomorphic and polymorphic tachycardia) were commonly observed. After washout of rapamycin and isoproterenol, no triggered activity was observed. Surprisingly, triggered activity and SCRs occurred preferentially near the epicardium but not the endocardium (P Ͻ 0.01). Interestingly, the occurrence of triggered activity and SCR events could not be explained by cytoplasmic calcium levels, but rather by fast calcium reuptake kinetics. These data suggest that, under abnormal RyR conditions, triggered activity is caused by multiple SCR events that depend on the faster calcium reuptake kinetics near the epicardium. Furthermore, multiple regions of SCR may be a mechanism for multifocal arrhythmias associated with RyR dysfunction. spontaneous calcium release; sudden death; arrhythmia mechanisms ARRHYTHMIAS CAUSED BY ABNORMAL impulse formation (i.e., triggered activity) have been associated with (33, 34) and without (5, 9, 16, 27) structural heart disease. In addition, recent evidence suggests that such arrhythmias can be caused by spontaneous calcium release (SCR) from the sarcoplasmic reticulum (SR). SCR events may be a result of cardiac ryanodine receptor (RyR) dysfunction such as that associated with mutations in the human cardiac RyR channel (37), heart failure (25, 40), and/or alterations in the RyR (30) and accessory proteins (e.g., FKBP12.6) (45, 49); however, the underlying mechanisms are controversial. FKBP12.6 is an accessory protein to the tetrameric RyR channel with 4:1 stoichiometry that stabilizes the RyR in the closed/open state and prevents aberrant activation during diastole. Dissociation of the FKBP12.6 molecule is believed to cause RyR channels to gate independently and alter individual RyR channel gating kinetics, rendering the channel prone to SCR events (28). Alternatively, SCR associated with abn...

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“…2). This is in agreement with experimental findings (22,45) and the clinical manifestation of the disease condition seen in patients (17,26,36,39).…”

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Ryanodine receptor dysfunction and triggered activity in the heart

Katra¹,

Oya²,

Hoeker³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…14 Recently, the Brugada syndrome has been linked to abnormalities of the sodium channel, 3,15 and mutations in the ryanodine receptor have been implicated in sudden death in families with familial polymorphous ventricular tachycardia. 16,17 Ryanodine receptor mutations result in increased sensitivity of calcium-induced activation of the calcium-release (L-type calcium channel) complex, without long-QT intervals. The diverse genetic defects related to cardiac ion channels may lead to lethal ventricular arrhythmias in the absence of any morphological findings in the heart or conduction system at autopsy.…”

Section: Discussionmentioning

confidence: 99%

Role of SCN5A Y1102 Polymorphism in Sudden Cardiac Death in Blacks

et al. 2005

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Background-The Y1102 polymorphism of the cardiac sodium channel (SCN5A) gene has been found in 13% of black Americans. It has been linked to lethal arrhythmias in black families with ventricular tachycardia. The prevalence of the Y1102 polymorphism in a series of sudden death in blacks is unknown. Methods and Results-We investigated the incidence of the Y1102 polymorphism in a series of 289 sudden deaths in blacks by sequencing an amplified segment of DNA that contained the polymorphic site extracted from prospectively sampled frozen splenic tissue. The deaths were classified as noncardiac controls (nϭ107), cardiac arrhythmias with clear anatomic substrate (nϭ117), cardiac arrhythmias with no anatomic substrate except mild to moderate cardiac hypertrophy (nϭ40), and unexplained cardiac arrhythmias (nϭ25). Cause of death was determined after complete forensic autopsy and postmortem cardiac examination. The overall frequency of the Y1102 polymorphism was 9.0%. The frequency was 5.6% in noncardiac deaths, 4.3% in cardiac deaths with obvious anatomic substrate, 20.0% in arrhythmias with moderate hypertrophy, and 28% in unexplained arrhythmias. Adjusted for age and sex, the relative risk of an unexplained arrhythmic death was 8.

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“…It is widely believed that the isoleucine-proline (residues 2427 and 2428) motif constitutes an essential part of the FKBP12.6 binding site in RyR2 (14,18,(31)(32)(33). This belief stems mainly from the observation that a small fragment of RyR2 encompassing this motif interacts with FKBP12.6 in the yeast two-hybrid assay and that the corresponding motif in RyR1, RyR3, and IP3R is critical for FKBP12 and FKBP12.6 binding (10,12,14,19,20).…”

Section: Discussionmentioning

confidence: 99%

Localization of the 12.6-kDa FK506-binding Protein (FKBP12.6) Binding Site to the NH2-terminal Domain of the Cardiac Ca2+ Release Channel (Ryanodine Receptor)

Masumiya¹,

Wang

Zhang

et al. 2003

Journal of Biological Chemistry

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The 12.6-kDa FK506-binding protein (FKBP12.6) interacts with the cardiac ryanodine receptor (RyR2) and modulates its channel function. However, the molecular basis of FKBP12.6-RyR2 interaction is poorly understood. To investigate the significance of the isoleucineproline (residues 2427-2428) dipeptide epitope, which is thought to form an essential part of the FKBP12.6 binding site in RyR2, we generated single and double mutants, P2428Q, I2427E/P2428A, and P2428A/L2429E, expressed them in HEK293 cells, and assessed their ability to bind GST-FKBP12.6. None of these mutations abolished GST-FKBP12.6 binding, indicating that this isoleucine-proline motif is unlikely to form the core of the FKBP12.6 binding site in RyR2. To systematically define the molecular determinants of FKBP12.6 binding, we constructed a series of internal and NH 2 -and COOHterminal deletion mutants of RyR2 and examined the effect of these deletions on GST-FKBP12.6 binding. These deletion analyses revealed that the first 305 NH 2 -terminal residues and COOH-terminal residues 1937-4967 are not essential for GST-FKBP12.6 binding, whereas multiple sequences within a large region between residues 305 and 1937 are required for GST-FKBP12.6 interaction. Furthermore, an NH 2 -terminal fragment containing the first 1937 residues is sufficient for GST-FKBP12.6 binding. Co-expression of overlapping NH 2 and COOH-terminal fragments covering the entire sequence of RyR2 produced functional channels but did not restore GST-FKBP12.6 binding. These data suggest that FKBP12.6 binding is likely to be conformationdependent. Binding of FKBP12.6 to the NH 2 -terminal domain may play a role in stabilizing the conformation of this region.

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Clinical Implications of Cardiac Ryanodine Receptor/Calcium Release Channel Mutations Linked to Sudden Cardiac Death

Cited by 33 publications

References 36 publications

Ryanodine receptor dysfunction and triggered activity in the heart

Ryanodine receptor dysfunction and triggered activity in the heart

Role of SCN5A Y1102 Polymorphism in Sudden Cardiac Death in Blacks

Localization of the 12.6-kDa FK506-binding Protein (FKBP12.6) Binding Site to the NH2-terminal Domain of the Cardiac Ca2+ Release Channel (Ryanodine Receptor)

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