Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death

Mohler, Peter J.; Schott, Jean‐Jacques; Gramolini, Anthony O.; Dilly, Keith W.; Guatimosim, Sílvia; duBell, William H.; Song, Long‐Sheng; Haurogné, Karine; Kyndt, Florence; Ali, Mervat; Rogers, Terry B.; Lederer, W. Jonathan; Escande, Denis; Marec, Hervé Le; Bennett, Vann

doi:10.1038/nature01335

Cited by 877 publications

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“…To date, however, high resolution electron micrographs have not specifically revealed such an organization -nor have they denied it. Nevertheless, RyR2s are organized tightly with LTCCs as shown by the Moore group [26], a requirement for local control of EC coupling [27][28][29], while our group and others have demonstrated that IP 3 Rs, ankyrin-B, Na + /K + ATPase, Na + /Ca 2+ exchanger and Na + channels (Na v 1.5) are co-localized nearby at the Z-line [16,17,30,31]. These findings suggest a spatial organization shown in Fig.…”

supporting

confidence: 57%

“…The subcellular localization of IP 3 Rs in cardiac myocytes has received increasing attention as the field attempts to define the function of these channels. In ventricular myocytes, immunofluorescence studies show that IP 3 Rs are found at the Z-lines, in the perinuclear region and in the nuclear membrane [7,16,17]. Moreover, IP 3 Rs are found in similar locations in both atrial [12] and Purkinje myocytes [18][19][20]).…”

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confidence: 99%

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The cardiac IP3 receptor: Uncovering the role of “the other” calcium-release channel

Hund

Ziman

Lederer

et al. 2008

Journal of Molecular and Cellular Cardiology

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Normal cardiac function relies on the tight coupling of functionally-related ion channels and transporters in the sarcolemma (plasma membrane and transverse-tubule network, TTs) with calcium-release channels (ryanodine receptors, type 2, RyR2) in the sarcoplasmic reticulum (SR), the intracellular Ca 2+ storage organelle (reviewed in [1]). Cardiac excitation-contraction (EC) coupling is initiated by membrane depolarization during the action potential (AP) that activates voltage-gated L-type Ca 2+ channels (LTCC) in the sarcolemma. The small increase in local [Ca 2+ ] i due to the Ca 2+ flux through the plasma membrane Ca 2+ channels is detected by nearby (15 nm) clusters of RyR2s in the junctional SR (jSR) to produce Ca 2+ sparks. This amplification system (termed "Ca 2+ -induced Ca 2+ release" or CICR) operates at high gain with great stability and is referred to as "local control" because there is a high [Ca 2+ ] i only locally between the LTCC and the jSR (in small space between them called the "subspace") [2][3][4]. The synchronization of Ca 2+ sparks by the AP produces the cell-wide [Ca 2+ ] i transient that activates contraction. Instability in cardiac Ca 2+ management may be due to altered RyR sensitivity ("RyR2 tuning" -see [2,5]), altered spatial organization of local Ca 2+ release sites, or mutations and variants of the RyR2 protein (as those found in specific diseases such as catecholaminergic polymorphic ventricular tachycardia). These changes in cardiac Ca 2+ signaling may result in defects in myocyte electrical activity and multiple human cardiac disease phenotypes, including arrhythmia, myopathy, and heart failure [6].While RyR2 Ca 2+ release channels have received significant attention by molecular cardiologists, in the past five years the role of a second pathway for internal Ca 2+ -release has largely been ignored. Specifically, the cellular role(s) for inositol 1,4,5-trisphosphate receptors (IP 3 R) have remained elusive. However, there is great and growing interest in cardiac IP 3 signaling due to the known importance of several IP 3 -inducing agonists (e.g. angiotensin II, endothelin, and norepinephrine) in hypertrophy and heart failure [7][8][9][10][11][12][13][14][15].While agonist-induced IP 3 -dependent Ca 2+ release is readily observed in most tissues, the role of IP 3 Rs in cardiac tissue is less clear. The subcellular localization of IP 3 Rs in cardiac myocytes has received increasing attention as the field attempts to define the function of these channels. In ventricular myocytes, immunofluorescence studies show that IP 3 Rs are found at the Z-lines, in the perinuclear region and in the nuclear membrane [7,16,17]. Moreover, IP 3 Rs are found

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confidence: 57%

mentioning

confidence: 99%

The cardiac IP3 receptor: Uncovering the role of “the other” calcium-release channel

Hund

Ziman

Lederer

et al. 2008

Journal of Molecular and Cellular Cardiology

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“…Consistent with this notion, IP 3 Rs have been localized close to the dyadic junctions where excitation-contraction coupling is initiated [142], and direct activation of IP 3 Rs was found to enhance Ca 2+ spark occurrence throughout ventricular cells [41]. Furthermore, application of hormones that activate the production of IP 3 inside ventricular myocytes, such as endothelin-1 [11], enhances systolic Ca 2+ signals in rat and rabbit cells [41,128,143].…”

Section: Ip 3 Signaling In Ventricular Myocytesmentioning

confidence: 62%

“…High affinity interaction between ankyrin-B and IP 3 R is required for posttranslational stability and targeting of the IP 3 R to SR microdomains closely opposed to neighboring T tubules [178,179]. Loss-of-function mutations in ankyrin-B cause reduction of IP 3 Rs in specialized SR-T tubule junctions (distinct from the classical dyads) in cardiac myocytes and are associated with arrhythmias ranging from bradycardia, sinus arrhythmia, atrial fibrillation and catecholaminergic polymorphic ventricular tachycardia to ventricular fibrillation both in humans and in mice heterozygous for a null mutation in ankyrin-B (ankyrin-B +/− mice) [142,180]. In patients affected by ankyrin-B mutations, emotional or physical stress may lead to syncopes and sudden death.…”

Section: Arrhythmias Related To Ankyrin-b Mutationsmentioning

confidence: 99%

“…Loss-of-function mutations in ankyrin-B disrupt this macromolecular complex. Cardiac myocytes from ankyrin-B +/− mice exhibit normal resting [Ca 2+ ] levels and unaltered L-type Ca 2+ currents but increased Ca 2+ transients and an increased propensity toward catechola-mine-induced arrhythmogenic SR Ca 2+ release [142] pointing to SR Ca 2+ overload as a causative factor. It has been suggested that IP 3 Rs act as "Ca 2+ pressure valves" releasing Ca 2+ from the SR, which is subsequently eliminated by the nearby NCX [179].…”

Section: Arrhythmias Related To Ankyrin-b Mutationsmentioning

confidence: 99%

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Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Kockskämper

Zima

Roderick

et al. 2008

Journal of Molecular and Cellular Cardiology

172

149

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Inositol 1,4,5-trisphosphate (IP 3 ) is a ubiquitous intracellular messenger regulating diverse functions in almost all mammalian cell types. It is generated by membrane receptors that couple to phospholipase C (PLC), an enzyme which liberates IP 3 from phosphatidylinositol 4,5-bisphosphate (PIP 2 ). The major action of IP 3 , which is hydrophilic and thus translocates from the membrane into the cytoplasm, is to induce Ca 2+ release from endogenous stores through IP 3 receptors (IP 3 Rs). Cardiac excitation-contraction coupling relies largely on ryanodine receptor (RyR)-induced Ca 2+ release from the sarcoplasmic reticulum. Myocytes express a significantly larger number of RyRs compared to IP 3 Rs (∼100:1), and furthermore they experience substantial fluxes of Ca 2+ with each heartbeat. Therefore, the role of IP 3 and IP 3 -mediated Ca 2+ signaling in cardiac myocytes has long been enigmatic. Recent evidence, however, indicates that despite their paucity cardiac IP 3 Rs may play crucial roles in regulating diverse cardiac functions. Strategic localization of IP 3 Rs in cytoplasmic compartments and the nucleus enables them to participate in subsarcolemmal, bulk cytoplasmic and nuclear Ca 2+ signaling in embryonic stem cell-derived and neonatal cardiomyocytes, and in adult cardiac myocytes from the atria and ventricles. Intriguingly, expression of both IP 3 Rs and membrane receptors that couple to PLC/IP 3 signaling is altered in cardiac disease such as atrial fibrillation or heart failure, suggesting the involvement of IP 3 signaling in the pathology of these diseases. Thus, IP 3 exerts important physiological and pathological functions in the heart, ranging from the regulation of pacemaking, excitation-contraction and excitation-transcription coupling to the initiation and/or progression of arrhythmias, hypertrophy and heart failure. KeywordsInositol 1,4,5-trisphosphate; Cardiac myocyte; Calcium; Inotropy; Arrhythmias; Nucleus; Hypertrophy © 2008 Elsevier Inc. All rights reserved. * Corresponding author. E-mail address: jens.kockskaemper@meduni-graz.at (J. Kockskämper).. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript The discovery of IP 3A quarter of a century ago it was shown that D-myo inositol 1,4,5-trisphosphate (IP 3 ) releases Ca 2+ from a non-mitochondrial internal Ca 2+ store [1]. Since this hallmark discovery, IP 3 has emerged as a ubiquitous intracellular messenger, releasing Ca 2+ from stores through activation of IP 3 receptors (IP 3 Rs) in almost all eukaryotic cells. The major IP 3 -sensitive intracellular Ca 2+ store is the endoplasmic reticulum. However, IP 3 has also been shown to release Ca 2+ stored in other compartments, such as the Golgi and the nuclear envelope [2]. In addition, IP 3 Rs are present on the plasma membrane of some cell types, where they can gate Ca 2+ influx [3]. A crucial role for IP 3 -dependent Ca 2+ release has been demonstrated in many mammalian cell types, ranging from tiny platelets, where it initiates blood clottin...

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Channels and Disease

Ptáček

Fu²

2004

Arch Neurol

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pisodic neurological phenotypes make up an interesting and important group of diseases affecting humans. These include disorders of the skeletal and cardiac muscles, peripheral nerves, and brain. They range from episodic weakness syndromes to rare paroxysmal movement disorders. More common episodic phenomena include cardiac arrhythmias, epilepsy syndromes, and headache. Molecular characterization of these disorders is shedding light on their pathophysiologic features and will ultimately lead to better diagnosis and treatment of patients.

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Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death

Cited by 877 publications

References 18 publications

The cardiac IP3 receptor: Uncovering the role of “the other” calcium-release channel

The cardiac IP3 receptor: Uncovering the role of “the other” calcium-release channel

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Channels and Disease

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