Mutations in the Cardiac L-Type Calcium Channel Associated with Inherited Sudden Cardiac Death Syndromes

Burashnikov, Elena; Pfeiffer, Ryan; Barajas-Martínez, Héctor; Delpón, Eva; Hu, Dan; Desai, Mayurika; Borggrefe, Martin; Haı̈ssaguerre, Michel; Kanter, Ronald J.; Pollevick, Guido D.; Guerchicoff, Alejandra; Laiño, Rubén; Marieb, Mark; Nademanee, Koonlawee; Nam, Gi‐Byoung; Monreal-Robles, Roberto; Schimpf, Rainer; Stapleton, Dwight H.; Viskin, Sami; Winters, Stephen L.; Wolpert, Christian; Zimmern, Samuel H.; Veltmann, Christian; Antzelevitch, Charles

doi:10.1016/j.hrthm.2010.09.053

Cited by 12 publications

(14 citation statements)

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“…No functional studies are available for this variant. Preliminary results indicate a loss-offunction mutation in CACNB2B, an accessory Ca 2ϩ -channel subunit, in 1 of 8 genotyped ER patients (43).…”

Section: Possible Underlying Mechanismsmentioning

confidence: 87%

“…To generate the typical ER pattern, it is necessary that some regions of the myocardium repolarize earlier than others: generalized ER would cause uniform shortening of the QTinterval, not the ST-segment elevation and J waves that characterize ER. Variations in a variety of currents can contribute to such repolarization differences (39)(40)(41)(42)(43). Figure 3 represents the principal ionic currents involved in the cardiac AP.…”

Section: Patient Managementmentioning

confidence: 99%

“…Presumed loss-of-function mutations in Ca 2ϩ -channels have been described in BrS, SQTS, and ER syndrome (43,53). Gain-of-function mutations in I Kr and I Ks subunits, classically related to SQTS, were recently also associated with ER (62,63).…”

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confidence: 99%

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Clinical and Mechanistic Issues in Early Repolarization

Benito

Guasch

Rivard

et al. 2010

Journal of the American College of Cardiology

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Early repolarization, involving ST-segment elevation and, sometimes, prominent J waves at the QRS-ST junction, has been considered a normal electrocardiographic variant for over 60 years. A growing number of case reports and case-control studies indicate that in some instances, early repolarization patterns are associated with increased risk of idiopathic ventricular fibrillation. Epidemiological evidence indicates a dose effect for the risk of cardiac and sudden death with the extent of J-point elevation. This paper reviews present knowledge regarding the epidemiology, presentation, therapeutic response, and mechanisms characteristic of early repolarization. We highlight major unanswered questions relating to our limited ability to determine which individuals with this common electrocardiographic variant are at risk for sudden death, our incomplete understanding of underlying mechanisms, the inadequate information regarding genetic determinants and therapeutic responses, and the unclear relationship between early repolarization and other conditions involving accelerated repolarization and sudden arrhythmic death such as Brugada and short-QT syndromes. This review paper intends to inform the practicing physician about important clinical issues and to stimulate investigators to address the many unresolved questions in this rapidly evolving field.

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Section: Possible Underlying Mechanismsmentioning

confidence: 87%

Section: Patient Managementmentioning

confidence: 99%

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Clinical and Mechanistic Issues in Early Repolarization

Benito

Guasch

Rivard

et al. 2010

Journal of the American College of Cardiology

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“…93 Last, mutations in the CACNA2D1 gene might be associated with some forms of cardiac dysfunction, including the Brugada and long QT syndromes. 94,95 Interestingly, it has been reported that experimental peripheral nerve injury results in increased levels of Ca V α 2 δ-1 mRNA in damaged dorsal root ganglion (DRG) sensory neurons, as well as a corresponding increase in protein levels in the neuronal cell bodies and at their presynaptic terminals in the spinal cord. [96][97][98] Furthermore, mice overexpressing the Ca V α 2 δ-1 subunit show a neuropathic phenotype of hyperalgesia and tactile allodynia in the absence of nerve injury, 99 suggesting that Ca V α 2 δ-1 is instrumental to the excitability of DRG neurons and the expression of neuropathic pain.…”

Section: The Ca V α 2 δ Subunitsmentioning

confidence: 99%

Regulation of high‐voltage‐activated Ca²⁺ channel function, trafficking, and membrane stability by auxiliary subunits

Felix

Calderón-Rivera

Andrade

2013

WIREs Membr Transp Signal

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Voltage-gated Ca2+ (CaV) channels mediate Ca2+ ions influx into cells in response to depolarization of the plasma membrane. They are responsible for initiation of excitation-contraction and excitation-secretion coupling, and the Ca2+ that enters cells through this pathway is also important in the regulation of protein phosphorylation, gene transcription, and many other intracellular events. Initial electrophysiological studies divided CaV channels into low-voltage-activated (LVA) and high-voltage-activated (HVA) channels. The HVA CaV channels were further subdivided into L, N, P/Q, and R-types which are oligomeric protein complexes composed of an ion-conducting CaVα1 subunit and auxiliary CaVα2δ, CaVβ, and CaVγ subunits. The functional consequences of the auxiliary subunits include altered functional and pharmacological properties of the channels as well as increased current densities. The latter observation suggests an important role of the auxiliary subunits in membrane trafficking of the CaVα1 subunit. This includes the mechanisms by which CaV channels are targeted to the plasma membrane and to appropriate regions within a given cell. Likewise, the auxiliary subunits seem to participate in the mechanisms that remove CaV channels from the plasma membrane for recycling and/or degradation. Diverse studies have provided important clues to the molecular mechanisms involved in the regulation of CaV channels by the auxiliary subunits, and the roles that these proteins could possibly play in channel targeting and membrane Stabilization.

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“…Only sporadic variants of KCNJ8, CACNA1C, and CACNB2B have been reported in patients with ER and VF. 30,31 SUMMARY Current scientific evidence drawn from a large cohort of subjects with long-term follow-up suggests that J-wave elevation in the inferolateral leads is not always benign. There is a high prevalence of ER in patients experiencing first, recurrent, and stormy episodes of idiopathic VF.…”

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confidence: 99%

Early Repolarization Disease

Sacher

Chatel

Derval

et al. 2010

Cardiac Electrophysiology Clinics

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Mutations in the Cardiac L-Type Calcium Channel Associated with Inherited Sudden Cardiac Death Syndromes

Cited by 12 publications

References 0 publications

Clinical and Mechanistic Issues in Early Repolarization

Clinical and Mechanistic Issues in Early Repolarization

Regulation of high‐voltage‐activated Ca²⁺ channel function, trafficking, and membrane stability by auxiliary subunits

Early Repolarization Disease

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Mutations in the Cardiac L-Type Calcium Channel Associated with Inherited Sudden Cardiac Death Syndromes

Cited by 12 publications

References 0 publications

Clinical and Mechanistic Issues in Early Repolarization

Clinical and Mechanistic Issues in Early Repolarization

Regulation of high‐voltage‐activated Ca2+ channel function, trafficking, and membrane stability by auxiliary subunits

Early Repolarization Disease

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Product

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Regulation of high‐voltage‐activated Ca²⁺ channel function, trafficking, and membrane stability by auxiliary subunits