ArticleThe Journal of physiology2009
The Timothy syndrome mutation of cardiac CaV1.2 (L-type) channels: multiple altered gating mechanisms and pharmacological restoration of inactivation.
Article in The Journal of physiology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed.
- Inactivation of CaV1 and CaV2 channels.The Journal of general physiology · 2025Review
- CACNA1C-Related Channelopathies.Handbook of experimental pharmacology · 2023Review
- Characterizing Genotypes and Phenotypes Associated with Dysfunction of Channel-Encoding Genes in a Cohort of Patients with Intellectual Disability.Archives of Iranian medicine · 2022Article
- Impaired CaJournal of molecular and cellular cardiology · 2022Article
- CaV1.2 channelopathic mutations evoke diverse pathophysiological mechanisms.The Journal of general physiology · 2022Article
- Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives.Molecules (Basel, Switzerland) · 2022Review
- Suppression of ventricular arrhythmias by targeting late L-type Ca2+ current.The Journal of general physiology · 2021Article
- L-type channel inactivation balances the increased peak calcium current due to absence of Rad in cardiomyocytes.The Journal of general physiology · 2021Article
- Drug Development and the Use of Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Disease Modeling and Drug Toxicity Screening.International journal of molecular sciences · 2020Review
- Cav1.2 channelopathies causing autism: new hallmarks on Timothy syndrome.Pflugers Archiv : European journal of physiology · 2020Review
- Dysfunctional Cav1.2 channel in Timothy syndrome, from cell to bedside.Experimental biology and medicine (Maywood, N.J.) · 2019Article
- Calcium-dependent inactivation controls cardiac L-type CaThe Journal of general physiology · 2019Article
- Impaired chromaffin cell excitability and exocytosis in autistic Timothy syndrome TS2-neo mouse rescued by L-type calcium channel blockers.The Journal of physiology · 2019Article
- α-Neurexins Together with α2δ-1 Auxiliary Subunits Regulate CaThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia.Channels (Austin, Tex.) · 2018Review
- Human pluripotent stem cell models of cardiac disease: from mechanisms to therapies.Disease models & mechanisms · 2017Review
- Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome.Stem cell reports · 2017Article
- Molecular Pathophysiology of Congenital Long QT Syndrome.Physiological reviews · 2017Review
- Computational Cardiac Modeling Reveals Mechanisms of Ventricular Arrhythmogenesis in Long QT Syndrome Type 8:Frontiers in physiology · 2017Article
- Cardiac arrest refractory to standard intervention in atypical Timothy syndrome (LQT8 type 2).Proceedings (Baylor University. Medical Center) · 2016Article
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4 authors.
Funding
Abstract
Timothy syndrome (TS) is a multiorgan dysfunction caused by a Gly to Arg substitution at position 406 (G406R) of the human CaV1.2 (L-type) channel. The TS phenotype includes severe arrhythmias that are thought to be triggered by impaired open-state voltage-dependent inactivation (OSvdI). The effect of the TS mutation on other L-channel gating mechanisms has yet to be investigated. We compared kinetic properties of exogenously expressed (HEK293 cells) rabbit cardiac L-channels with (G436R; corresponding to position 406 in human clone) and without (wild-type) the TS mutation. Our results surprisingly show that the TS mutation did not affect close-state voltage-dependent inactivation, which suggests different gating mechanisms underlie these two types of voltage-dependent inactivation. The TS mutation also significantly slowed activation at voltages less than 10 mV, and significantly slowed deactivation across all test voltages. Deactivation was slowed in the double mutant G436R/S439A, which suggests that phosphorylation of S439 was not involved. The L-channel agonist Bay K8644 increased the magnitude of both step and tail currents, but surprisingly failed to slow deactivation of TS channels. Our mathematical model showed that slowed deactivation plus impaired OSvdI combine to synergistically increase cardiac action potential duration that is a likely cause of arrhythmias in TS patients. Roscovitine, a tri-substituted purine that enhances L-channel OSvdI, restored TS-impaired OSvdI. Thus, inactivation-enhancing drugs are likely to improve cardiac arrhythmias and other pathologies afflicting TS patients.
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