CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism

Department of Cardiology, Children's Hospital, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA.
Cell (Impact Factor: 32.24). 11/2004; 119(1):19-31. DOI: 10.1016/j.cell.2004.09.011
Source: PubMed


Ca(V)1.2, the cardiac L-type calcium channel, is important for excitation and contraction of the heart. Its role in other tissues is unclear. Here we present Timothy syndrome, a novel disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. In every case, Timothy syndrome results from the identical, de novo Ca(V)1.2 missense mutation G406R. Ca(V)1.2 is expressed in all affected tissues. Functional expression reveals that G406R produces maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation. This likely induces intracellular Ca(2+) overload in multiple cell types. In the heart, prolonged Ca(2+) current delays cardiomyocyte repolarization and increases risk of arrhythmia, the ultimate cause of death in this disorder. These discoveries establish the importance of Ca(V)1.2 in human physiology and development and implicate Ca(2+) signaling in autism.

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    • "Do VDI and CDI share a final common pathway, or are they mediated independently (Findlay, 2004; Kim et al., 2004; Barrett and Tsien, 2008)? For example, in LQT8 or Timothy's syndrome, mutations in Ca v 1.2 specifically impair VDI, leading to AP duration prolongation and EADs (Splawski et al., 2004). The study by Madhvani et al. (2015) does not distinguish the respective roles of VDI and CDI in the late I Ca,L , which is modeled as a constant. "

    The Journal of General Physiology 06/2015; 145(6):475-9. DOI:10.1085/jgp.201511429 · 4.79 Impact Factor
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    • "In fact, mutations in I Ks that disrupt CaM binding result in decreased K current, thus causing LQTS [43] [46]. More broadly, because CaM regulates many other Ca 2+ channel subtypes, including those predominate in neurons and immune cells, disruption of CDI could lead to a multi-system disorder similar to Timothy syndrome [47] [48] [49]. It may well be that extra-cardiac effects are also present in patients possessing LQTS CaM mutants, but that these effects were not recognized in the face of immediately life-threatening cardiac-related sequelae. "
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    ABSTRACT: Sodium channel mutations near the IQ and EFL motifs in the carboxyterminal (CT) domain have been linked to long QT (LQTS) and Brugada syndromes (BrS). IQ-calmodulin (CaM) interaction is important for regulation of cardiac Na channels. The aim of this study was to assess the role of CaM mediated regulation of cardiac Na+ channels via the IQ motif in development and maturation of intercalated disc (ID). We studied transgenic mice with alanines knocked into IQ positions in the Nav1.5 CT. The homozygous mice are embryonic lethal and heterozygous mice (IQ/AA+/- mice), develop cardiomyopathy (DCM). We measured the signal and distribution of Nav1.5, syntrophin, Cx43 and ryanodine in 3, 6 and 9 month old IQ/AA+/- mice. Results were compared to those obtained from age matched wild type mice. By immunohistochemistry we show that Nav1.5 protein in 9 month-old IQ/AA+/- mice is significantly reduced at the ID. Syntrophin that traffics Na channels to the membrane, is not altered. Cx43 which is co-located with Nav1.5 at the ID, is significantly reduced. The expression of these proteins were not altered in 3 month-old IQ/AA+/- mice. We also assessed the role of the IQ domain on the localization of Ca2+ handling proteins such as the ryanodine receptor and found that it was not altered in 9 month-old IQ/AA+/- mice. The data suggest that enhanced late INa,L in IQ/AA+/- mice contributes to DCM via remodeling of electrical and junctional proteins and demonstrate a dynamic interplay of CaM and Na+ channels via the IQ motif in ID development and maturation. Our study highlights the importance of CaM-mediated regulation of Na+ channels in DCM and arrhythmia.
    Biophysical Meeting, Baltimore, MD; 02/2015
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    • "Inhibition of ICa inactivation induces AP prolongation, and has pro-arrhythmic consequences (see section “Arrhythmogenic consequences of CaMKII-dependent ICa effects”). For example, impaired VDI has been observed in Timothy syndrome (Splawski et al., 2004, 2005; Brunet et al., 2009), an inherited disease characterized by severe ventricular arrhythmias and sudden cardiac death. The expression of mutant Ca2+-insensitive CaM (via adenovirus) in adult guinea-pig cardiomyocytes also prevents CDI and causes dramatic AP prolongation (Alseikhan et al., 2002). "
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    ABSTRACT: The cardiac voltage gated Ca(2+) current (ICa) is critical to the electrophysiological properties, excitation-contraction coupling, mitochondrial energetics, and transcriptional regulation in heart. Thus, it is not surprising that cardiac ICa is regulated by numerous pathways. This review will focus on changes in ICa that occur during the cardiac action potential (AP), with particular attention to Ca(2+)-dependent inactivation (CDI), Ca(2+)-dependent facilitation (CDF) and how calmodulin (CaM) and Ca(2+)-CaM dependent protein kinase (CaMKII) participate in the regulation of Ca(2+) current during the cardiac AP. CDI depends on CaM pre-bound to the C-terminal of the L-type Ca(2+) channel, such that Ca(2+) influx and Ca(2+) released from the sarcoplasmic reticulum bind to that CaM and cause CDI. In cardiac myocytes CDI normally pre-dominates over voltage-dependent inactivation. The decrease in ICa via CDI provides direct negative feedback on the overall Ca(2+) influx during a single beat, when myocyte Ca(2+) loading is high. CDF builds up over several beats, depends on CaMKII-dependent Ca(2+) channel phosphorylation, and results in a staircase of increasing ICa peak, with progressively slower inactivation. CDF and CDI co-exist and in combination may fine-tune the ICa waveform during the cardiac AP. CDF may partially compensate for the tendency for Ca(2+) channel availability to decrease at higher heart rates because of accumulating inactivation. CDF may also allow some reactivation of ICa during long duration cardiac APs, and contribute to early afterdepolarizations, a form of triggered arrhythmias.
    Frontiers in Pharmacology 06/2014; 5:144. DOI:10.3389/fphar.2014.00144 · 3.80 Impact Factor
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