ArticleMolecular pharmacology2015
Essential Role of Calmodulin in RyR Inhibition by Dantrolene.
Article in Molecular pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 73 citations in OpenAlex.
- Structural identification of the RY12 domain of RyR1 as an ADP sensor and the target of the malignant hyperthermia therapeutic dantrolene.Nature communications · 2026Article
- Catecholaminergic polymorphic ventricular tachycardia-linked ryanodine receptor variants exhibit domain-specific calcium leak and calmodulin affinity properties.The Journal of physiology · 2026Article
- Introduction of a single carboxylic acid converts the cyclic oligomeric depsipeptide ent-verticilide from a ryanodine receptor 2 (RyR2) inhibitor to RyR2 activator.Molecular pharmacology · 2025Article
- Crystal structures of Ryanodine Receptor reveal dantrolene and azumolene interactions guiding inhibitor development.Nature communications · 2025Article
- Calmodulin enhancement of mitochondrial calcium uniporter function in isolated mitochondria.Cell calcium · 2025Article
- Calcium Oscillations Within Juxtaglomerular Cell Clusters Control Renin Release.Circulation research · 2025Article
- SelK promotes glioblastoma cell proliferation by inhibiting β-TrCP1 mediated ubiquitin-dependent degradation of CDK4.Journal of experimental & clinical cancer research : CR · 2024Article
- Clustering properties of the cardiac ryanodine receptor in health and heart failure.Journal of molecular and cellular cardiology · 2023Review
- Dantrolene inhibition of ryanodine channels (RyR2) in artificial lipid bilayers depends on FKBP12.6.The Journal of general physiology · 2023Article
- Molecular Aspects Implicated in Dantrolene Selectivity with Respect to Ryanodine Receptor Isoforms.International journal of molecular sciences · 2023Article
- In-phasic cytosolic-nuclear CaFrontiers in neuroscience · 2023Article
- Emerging Antiarrhythmic Drugs for Atrial Fibrillation.International journal of molecular sciences · 2022Review
- Excitation-contraction coupling in mammalian skeletal muscle: Blending old and last-decade research.Frontiers in physiology · 2022Review
- Structural Insight Into Ryanodine Receptor Channelopathies.Frontiers in pharmacology · 2022Review
- Dantrolene repurposed to treat sepsis or septic shock and COVID-19 patients.European review for medical and pharmacological sciences · 2021Review
- Pathological conformations of disease mutant Ryanodine Receptors revealed by cryo-EM.Nature communications · 2021Article
- Limiting RyR2 Open Time Prevents Alzheimer's Disease-Related Neuronal Hyperactivity and Memory Loss but Not β-Amyloid Accumulation.Cell reports · 2020Article
- CaMKII-dependent ryanodine receptor phosphorylation mediates sepsis-induced cardiomyocyte apoptosis.Journal of cellular and molecular medicine · 2020Article
- Diurnal properties of voltage-gated CaThe Journal of physiology · 2020Article
- Targeting RyR Activity Boosts Antisense Exon 44 and 45 Skipping in Human DMD Skeletal or Cardiac Muscle Culture Models.Molecular therapy. Nucleic acids · 2019Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Dantrolene is the first line therapy of malignant hyperthermia. Animal studies suggest that dantrolene also protects against heart failure and arrhythmias caused by spontaneous Ca(2+) release. Although dantrolene inhibits Ca(2+) release from the sarcoplasmic reticulum of skeletal and cardiac muscle preparations, its mechanism of action has remained controversial, because dantrolene does not inhibit single ryanodine receptor (RyR) Ca(2+) release channels in lipid bilayers. Here we test the hypothesis that calmodulin (CaM), a physiologic RyR binding partner that is lost during incorporation into lipid bilayers, is required for dantrolene inhibition of RyR channels. In single channel recordings (100 nM cytoplasmic [Ca(2+)] + 2 mM ATP), dantrolene caused inhibition of RyR1 (rabbit skeletal muscle) and RyR2 (sheep) with a maximal inhibition of Po (Emax) to 52 ± 4% of control only after adding physiologic [CaM] = 100 nM. Dantrolene inhibited RyR2 with an IC50 of 0.16 ± 0.03 µM. Mutant N98S-CaM facilitated dantrolene inhibition with an IC50 = 5.9 ± 0.3 nM. In mouse cardiomyocytes, dantrolene had no effect on cardiac Ca(2+) release in the absence of CaM, but reduced Ca(2+) wave frequency (IC50 = 0.42 ± 0.18 µM, Emax = 47 ± 4%) and amplitude (IC50 = 0.19 ± 0.04 µM, Emax = 66 ± 4%) in the presence of 100 nM CaM. We conclude that CaM is essential for dantrolene inhibition of RyR1 and RyR2. Its absence explains why dantrolene inhibition of single RyR channels has not been previously observed.
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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.