Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome

Song, LouJin; Park, Seon-Hye E.; Isseroff, Yehuda; Morikawa, Kumi; Yazawa, Masayuki

doi:10.1016/j.stemcr.2017.05.028

Cited by 22 publications

(41 citation statements)

References 34 publications

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“…Although roscovitine rescued the electrophysiological abnormality in LQTS8 hiPSC-CMs, the exact mechanism by which it restored cardiac function was not clear. In a separate study 104 , it was shown that roscovitine exhibits its therapeutic effects in part by inhibiting CDK5, a key mediator involved in the regulation of Ca V 1.2 channels in CMs. These studies provide mechanistic insights into the regulation of Ca V 1.2 and the development of future therapeutics for Timothy syndrome patients 104 .…”

Section: Long Qt Syndromementioning

confidence: 99%

“…To date, several groups have successfully modeled CPVT using the hiPSC platform 106–108 . CPVT1 patient-specific hiPSC-CMs carrying the F2483I mutation in the RYR2 107 recapitulated DADs after catecholaminergic stimulation while Ca 2+ imaging studies revealed higher amplitudes and longer durations of spontaneous Ca 2+ release at basal state compared to control hiPSC-CMs.…”

Section: Catecholaminergic Polymorphic Ventricular Tachycardiamentioning

confidence: 99%

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Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes as Models for Cardiac Channelopathies

Garg

Shrestha

et al. 2018

Circulation Research

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Life threatening ventricular arrhythmias leading to sudden cardiac death are a major cause of morbidity and mortality. In the absence of structural heart disease, these arrhythmias, especially in the younger population, are often an outcome of genetic defects in specialized membrane proteins called ion channels. In the heart, exceptionally well-orchestrated activity of a diversity of ion channels mediates the cardiac action potential. Alterations in either the function or expression of these channels can disrupt the configuration of the action potential, leading to abnormal electrical activity of the heart that can sometimes initiate an arrhythmia. Understanding the pathophysiology of inherited arrhythmias can be challenging because of the complexity of the disorder and lack of appropriate cellular and in vivo models. Recent advances in human induced pluripotent stem cell technology have provided remarkable progress in comprehending the underlying mechanisms of ion channel disorders or channelopathies by modeling these complex arrhythmia syndromes in vitro in a dish. To fully realize the potential of induced pluripotent stem cells in elucidating the mechanistic basis and complex pathophysiology of channelopathies, it is crucial to have a basic knowledge of cardiac myocyte electrophysiology. In this review, we will discuss the role of the various ion channels in cardiac electrophysiology and the molecular and cellular mechanisms of arrhythmias, highlighting the promise of human induced pluripotent stem cell-cardiomyocytes as a model for investigating inherited arrhythmia syndromes and testing antiarrhythmic strategies. Overall, this review aims to provide a basic understanding of the electrical activity of the heart and related channelopathies, especially to clinicians or research scientists in the cardiovascular field with limited electrophysiology background.

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Section: Long Qt Syndromementioning

confidence: 99%

Section: Catecholaminergic Polymorphic Ventricular Tachycardiamentioning

confidence: 99%

Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes as Models for Cardiac Channelopathies

Garg

Shrestha

et al. 2018

Circulation Research

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“…In general, it appears that macroscopic gating changes observed in heterologous expression systems reproduce the changes observed in native cells reasonably well. This is evident from animal models harboring specific human mutations ( Drum et al, 2014 ; Rose et al, 2014 ; Calorio et al, 2019 ) or from human cells differentiated from patient-derived induced pluripotent stem cells (iPSCs; e.g., neuron-like or cardiomyocyte-like cells; Yazawa et al, 2011 ; Krey et al, 2013 ; Song et al, 2017 ; Estes et al, 2019 ; Chavali et al, 2019 ). In contrast, it is less clear how well changes of current density and of channel protein expression observed in heterologous overexpression systems reflect changes of current density in native tissues ( Chavali et al, 2019 ).…”

Section: Gain- and Loss- Of Ca 2+ -Channel Functiomentioning

confidence: 99%

“…Recently, crystal structures and homology modeling provided compelling evidence that this region binds SH3-domain-containing proteins (e.g., STAC) and LQT8 variants are expected to weaken this interaction ( Mellor et al, 2019 ). Another example is the slow inactivation of the Cav1.2-G406R type 1 mutation, which appears to be mediated by cyclin-dependent kinase 5 (CDK-5; Song et al, 2017 ).…”

Section: Gain- and Loss- Of Ca 2+ -Channel Functiomentioning

confidence: 99%

Voltage-Gated Ca2+-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function – Implications for Potential Therapies

Striessnig

2021

Front. Synaptic Neurosci.

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This review summarizes our current knowledge of human disease-relevant genetic variants within the family of voltage gated Ca2+ channels. Ca2+ channelopathies cover a wide spectrum of diseases including epilepsies, autism spectrum disorders, intellectual disabilities, developmental delay, cerebellar ataxias and degeneration, severe cardiac arrhythmias, sudden cardiac death, eye disease and endocrine disorders such as congential hyperinsulinism and hyperaldosteronism. A special focus will be on the rapidly increasing number of de novo missense mutations identified in the pore-forming α1-subunits with next generation sequencing studies of well-defined patient cohorts. In contrast to likely gene disrupting mutations these can not only cause a channel loss-of-function but can also induce typical functional changes permitting enhanced channel activity and Ca2+ signaling. Such gain-of-function mutations could represent therapeutic targets for mutation-specific therapy of Ca2+-channelopathies with existing or novel Ca2+-channel inhibitors. Moreover, many pathogenic mutations affect positive charges in the voltage sensors with the potential to form gating-pore currents through voltage sensors. If confirmed in functional studies, specific blockers of gating-pore currents could also be of therapeutic interest.

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“…60 Other study also demonstrated that roscovitine exerts its therapeutic effects partly by inhibiting CDK5, providing new evidences in regulating cardiac Cav1.2 channels and developing therapeutics for managing TS patients. 101…”

Section: Treatment and Managementmentioning

confidence: 99%

Dysfunctional Cav1.2 channel in Timothy syndrome, from cell to bedside

Han

Xue

Yan

et al. 2019

Exp Biol Med (Maywood)

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Timothy syndrome is a rare disorder caused by CACNA1C gene mutations and characterized by multi-organ system dysfunctions, including ventricular arrhythmias, syndactyly, dysmorphic facial features, intermittent hypoglycemia, immunodeficiency, developmental delay, and autism. Because of the low morbidity and high mortality at a young age, it remains a huge challenge to establish a diagnosis and treatment system to manage Timothy syndrome patients. Here, we aim to provide a detailed review of Timothy syndrome, discuss the mechanisms underlying dysfunctional Cav1.2 due to CACNA1C mutations, and provide some new emerging evidences in treating Timothy syndrome from cell to bedside, promoting the management of this rare disease. Impact statement The knowledge of Timothy syndrome (TS) caused by dysfunctional Cav1.2 channel due to CACNA1C mutations is rapidly evolving as novel technologies of electrophysiology are introduced and our understanding of the mechanisms of TS develops. In this review, we focus on the TS-related dysfunctional Cav1.2 and the underlying mechanisms. We update TS-related CACNA1C mutations in a precise way over the past 20 years and summarize all reported TS patients based on their clinical presentations and molecular mechanisms, respectively. We hope this review will provide a new comprehensive way to better understand the electrophysiological mechanisms underlying TS from cell to bedside, promoting the management of TS in practice.

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Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome

Cited by 22 publications

References 34 publications

Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes as Models for Cardiac Channelopathies

Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes as Models for Cardiac Channelopathies

Voltage-Gated Ca2+-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function – Implications for Potential Therapies

Dysfunctional Cav1.2 channel in Timothy syndrome, from cell to bedside

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