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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.<\/jats:p>","DOI":"10.1085\/jgp.202213277","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T02:20:42Z","timestamp":1684808442000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["Dantrolene inhibition of ryanodine channels (RyR2) in artificial lipid bilayers depends on FKBP12.6"],"prefix":"10.1085","volume":"155","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1866-5767","authenticated-orcid":true,"given":"Kafa","family":"Walweel","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute 1 , Callaghan, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8212-2209","authenticated-orcid":true,"given":"Nicole","family":"Beard","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04s1nv328","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Canberra 2 Faculty of Science and Technology, , Bruce, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5631-6579","authenticated-orcid":true,"given":"Dirk F.","family":"van Helden","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute 1 , Callaghan, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9919-7661","authenticated-orcid":true,"given":"Derek R.","family":"Laver","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute 1 , Callaghan, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2023,6,6]]},"reference":[{"key":"2023060620312912100_bib1","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/s0304-3940(97)00193-6","article-title":"Ryanodine receptors from rabbit skeletal muscle are reversibly activated by rapamycin","volume":"225","author":"Ahern","year":"1997","journal-title":"Neurosci. 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