ArticleThe Journal of general physiology2023
Dantrolene inhibition of ryanodine channels (RyR2) in artificial lipid bilayers depends on FKBP12.6.
Article in The Journal of general physiology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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7 citing papers in PubMed, 9 citations in OpenAlex.
- 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
- Investigation of the cardioprotective potential of dantrolene in mitigating arsenic-induced cardiac dysfunction in rats.Acta biochimica et biophysica Sinica · 2025Article
- Intranasal Dantrolene Nanoparticles for Treatment of Amyotrophic Lateral Sclerosis as a Disease-Modifying Drug.bioRxiv : the preprint server for biology · 2025Article
- Neuroprotective effects of dantrolene in neurodegenerative disease: Role of inhibition of pathological inflammation.Journal of anesthesia and translational medicine · 2024Article
- Article
- Clustering properties of the cardiac ryanodine receptor in health and heart failure.Journal of molecular and cellular cardiology · 2023Review
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Authors and funding
4 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Dantrolene is a neutral hydantoin that is clinically used as a skeletal muscle relaxant to prevent overactivation of the skeletal muscle calcium release channel (RyR1) in response to volatile anesthetics. Dantrolene has aroused considerable recent interest as a lead compound for stabilizing calcium release due to overactive cardiac calcium release channels (RyR2) in heart failure. Previously, we found that dantrolene produces up to a 45% inhibition RyR2 with an IC50 of 160 nM, and that this inhibition requires the physiological association between RyR2 and CaM. In this study, we tested the hypothesis that dantrolene inhibition of RyR2 in the presence of CaM is modulated by RyR2 phosphorylation at S2808 and S2814. Phosphorylation was altered by incubations with either exogenous phosphatase (PP1) or kinases; PKA to phosphorylate S2808 or endogenous CaMKII to phosphorylate S2814. We found that PKA caused selective dissociation of FKBP12.6 from the RyR2 complex and a loss of dantrolene inhibition. Rapamycin-induced FKBP12.6 dissociation from RyR2 also resulted in the loss of dantrolene inhibition. Subsequent incubations of RyR2 with exogenous FKBP12.6 reinstated dantrolene inhibition. These findings indicate that the inhibitory action of dantrolene on RyR2 depends on RyR2 association with FKBP12.6 in addition to CaM as previously found.
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