ArticleThe Journal of biological chemistry2010
Roscovitine binds to novel L-channel (CaV1.2) sites that separately affect activation and inactivation.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 36 citations in OpenAlex.
- Targeting mTOR in Systemic Lupus Erythematosus: From Immune Cell Dysfunction to Clinical Translation.Journal of inflammation research · 2026Review
- Inactivation of CaV1 and CaV2 channels.The Journal of general physiology · 2025Review
- CACNA1C-Related Channelopathies.Handbook of experimental pharmacology · 2023Review
- Impaired CaJournal of molecular and cellular cardiology · 2022Article
- Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives.Molecules (Basel, Switzerland) · 2022Review
- Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome.Molecular psychiatry · 2022Article
- Article
- Targeting late ICaL to close the window to ventricular arrhythmias.The Journal of general physiology · 2021Article
- Suppression of ventricular arrhythmias by targeting late L-type Ca2+ current.The Journal of general physiology · 2021Article
- Review
- 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
- R-Roscovitine Improves Motoneuron Function in Mouse Models for Spinal Muscular Atrophy.iScience · 2020Article
- Calcium Handling Defects and Cardiac Arrhythmia Syndromes.Frontiers in pharmacology · 2020Review
- ML277 specifically enhances the fully activated open state of KCNQ1 by modulating VSD-pore coupling.eLife · 2019Article
- Article
- Inhibition of CDK5 Alleviates the Cardiac Phenotypes in Timothy Syndrome.Stem cell reports · 2017Article
- Article
- Article
- Molecular Pathophysiology of Congenital Long QT Syndrome.Physiological reviews · 2017Review
- Calcium Revisited: New Insights Into the Molecular Basis of Long-QT Syndrome.Circulation. Arrhythmia and electrophysiology · 2016Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
L-type (Ca(V)1.2) calcium channel antagonists play an important role in the treatment of cardiovascular disease. (R)-Roscovitine, a trisubstituted purine, has been shown to inhibit L-currents by slowing activation and enhancing inactivation. This study utilized molecular and pharmacological approaches to determine whether these effects result from (R)-roscovitine binding to a single site. Using the S enantiomer, we find that (S)-roscovitine enhances inactivation without affecting activation, which suggests multiple sites. This was further supported in studies using chimeric channels comprised of N- and L-channel domains. Those chimeras containing L-channel domains I and IV showed (R)-roscovitine-induced slowed activation like that of wild type L-channels, whereas chimeric channels containing L-channel domain I responded to (R)-roscovitine with enhanced inactivation. We conclude that (R)-roscovitine binds to distinct sites on L-type channels to slow activation and enhance inactivation. These sites appear to be unique from other calcium channel antagonist sites that reside within domains III and IV and are thus novel sites that could be exploited for future drug development. Trisubstituted purines could become a new class of drugs for the treatment of diseases related to hyperfunction of L-type channels, such as Torsades de Pointes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.