The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2008; 105(6):2157-62. DOI: 10.1073/pnas.0710501105
Source: PubMed


Calcium entry into excitable cells is an important physiological signal, supported by and highly sensitive to the activity of voltage-gated Ca2+ channels. After membrane depolarization, Ca2+ channels first open but then undergo various forms of negative feedback regulation including voltage- and calcium-dependent inactivation (VDI and CDI, respectively). Inactivation of Ca2+ channel activity is perturbed in a rare yet devastating disorder known as Timothy syndrome (TS), whose features include autism or autism spectrum disorder along with severe cardiac arrhythmia and developmental abnormalities. Most cases of TS arise from a sporadic single nucleotide change that generates a mutation (G406R) in the pore-forming subunit of the L-type Ca2+ channel Ca(V)1.2. We found that the TS mutation powerfully and selectively slows VDI while sparing or possibly speeding the kinetics of CDI. The deceleration of VDI was observed when the L-type channels were expressed with beta1 subunits prominent in brain, as well as beta2 subunits of importance for the heart. Dissociation of VDI and CDI was further substantiated by measurements of Ca2+ channel gating currents and by analysis of another channel mutation (I1624A) that hastens VDI, acting upstream of the step involving Gly406. As highlighted by the TS mutation, CDI does not proceed to completeness but levels off at approximately 50%, consistent with a change in gating modes and not an absorbing inactivation process. Thus, the TS mutation offers a unique perspective on mechanisms of inactivation as well as a promising starting point for exploring the underlying pathophysiology of autism.

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    • "402; Splawski et al., 2004, 2005). These mutations profoundly impair voltage-dependent inactivation of I CaL (VDI), and this is generally accepted to be the proximal molecular dysfunction associated with the disease (Barrett and Tsien, 2008). The cardiac signatures of TS include a range of cardiac structural defects and markedly prolonged ventricular repolarization (Splawski et al., 2004, 2005). "
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    ABSTRACT: Calcium/calmodulin-dependent protein kinase II (CaMKII) activity has been shown to contribute to arrhythmogenesis in a remarkably broad range of cardiac pathologies. Several of these involve significant structural and electrophysiologic remodeling, whereas others are due to specific channelopathies, and are not typically associated with arrhythmogenic changes to protein expression or cellular and tissue structure. The ability of CaMKII to contribute to arrhythmia across such a broad range of phenotypes suggests one of two interpretations regarding the role of CaMKII in cardiac arrhythmia: (1) some CaMKII-dependent mechanism is a common driver of arrhythmia irrespective of the specific etiology of the disease, or (2) these different etiologies expose different mechanisms by which CaMKII is capable of promoting arrhythmia. In this review, we dissect the available mechanistic evidence to explore these two possibilities and discuss how the various molecular actions of CaMKII promote arrhythmia in different pathophysiologic contexts.
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    • "As would be predicted from the cardiac findings in this disorder, channel inactivation caused by changes in the membrane potential (referred to as voltage-dependent inactivation, VDI) are slowed, but there is additionally a different mechanism of inactivation regulated directly by calcium itself, and this process is greatly accelerated by the mutation. The net result of the mutant is a very rapid inactivation of half the current, and then a very slow inactivation of the remainder (Barrett and Tsien, 2008). "
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    ABSTRACT: Autism spectrum disorder (ASD) is a syndrome that affects normal brain development and is characterized by impaired social interaction as well as verbal and non-verbal communication and by repetitive, stereotypic behavior. ASD is a complex disorder arising from a combination of multiple genetic and environmental factors that are independent from racial, ethnic and socioeconomical status. The high heritability of ASD suggests a strong genetic basis for the disorder. Furthermore, a mounting body of evidence implies a role of various ion channel gene defects (channelopathies) in the pathogenesis of autism. Indeed, recent genome-wide association, and whole exome- and whole-genome resequencing studies linked polymorphisms and rare variants in calcium, sodium and potassium channels and their subunits with susceptibility to ASD, much as they do with bipolar disorder, schizophrenia and other neuropsychiatric disorders. Moreover, animal models with these genetic variations recapitulate endophenotypes considered to be correlates of autistic behavior seen in patients. An ion flux across the membrane regulates a variety of cell functions, from generation of action potentials to gene expression and cell morphology, thus it is not surprising that channelopathies have profound effects on brain functions. In the present work, we summarize existing evidence for the role of ion channel gene defects in the pathogenesis of autism with a focus on calcium signaling and its downstream effects.
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    • "By increasing Ca2+ influx through L-type VGCC, tosylchloramide is expected to prolong the plateau phase of cardiac action potential thus delaying cardiomyocyte repolarization and promoting the appearance of TdP. Intriguingly, an increase in L-type VGCC activity represents the mechanistic base of arrhythmias in LQT8 patients [28-30] bearing the Timothy syndrome mutations which cause an impairment in voltage-dependent CaV1.2 channel inactivation [31]. "
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    ABSTRACT: Background Drugs not commonly considered to be cardioactive agents may cause prolongation of the QT interval with resultant torsades de pointes and ventricular fibrillation. This form of drug toxicity often causes cardiac arrest or sudden death. Case presentation After accidental ingestion of tosylchloramide a caucasian 77-year-old woman, with a family history of cardiovascular disease and hypertension, was admitted to the intensive care unit following episodes of torsades de pointes with a prolonged QT/QTc interval (640/542 ms). The patient received an implantable cardioverter-defibrillator, was discharged from the hospital with normal QT/QTc interval and did not experience additional ventricular arrhythmias during one year of follow-up. Conclusion This is the first report concerning an unusual case of torsades de pointes after accidental intoxication by ingestion of tosylchloramide. The pronounced impact of the oxidyzing agent tosylchloramide on the activity of some of the ion channels regulating the QT interval was identified as a probable cause of the arrhythmia.
    Full-text · Article · Jan 2013 · BMC pharmacology & toxicology
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